Pharmacokinetics & Pharmaceutics Flashcards

Question

Freezing Point Depression

Answer 1

1. Dissolution of non-volatile solute in solvent decreases freezing point of solution with respect to that of the pure solvent 2. Kf is the freezing point depression constant: - characteristic for each solvent - independent of the solute

Answer 2

Osmotic pressure of a solution: external pressure needed to prevent the movement of solvent via osmosis. The pressure required to prevent water crossing a semi-permeable membrane.

Answer 3

For a non-electrolyte solution: Osmotic pressure (π) = (nRT)/V = cRT n = Number of moles R = Universal gas constant (8.31) T = Absolute temperature (K) V = volume (l)

Answer 4

For an electrolyte solution: In the case of an electrolyte, π depends on the total number of particles i.e., ions, in solution: e.g: CaCl2 reversible Ca2+ + 2Cl- Osmotic pressure (π) = i c R T van’t Hoff Factor (i)

Answer 5

1. For complete dissociation of MaXb, the number of ions in solution = number of ionic species in the salt, so i = a + b 2. Many salts do not completely dissociate, so i < a + b 3. Approximate values of “i” for practical purposes: 4. Non-electrolyte solutions i = 1 5. Dissociates into 2 ions i = 1.8 e.g. drug salts such as mono hydrochlorides 6. Dissociates into 3 ions i = 2.6 7. Dissociates into 4 ions i = 3.4

Answer 6

Osmolality = number of osmoles/kg of solvent (i.e., water) Osmolarity = number of osmoles/litre of solution Osmoles are “particles” and one osmole is: The amount of solute that will provide one Avogadro’s number of “particles”. The weight (in grams) of a solute which is osmotically equivalent to one mole of ideally-behaving non-electrolyte.

Answer 7

Isosmotic Solution (normal) πsolution = πintracellular Hyper-osmotic solution (shrivel) πsolution > πintracellular Hypo-osmotic solution (burst) πsolution < πintracellular

Answer 8

Isosmoticity: if two solutions are separated by a perfect semi-permeable membrane and there is no net movement of solvent, the solutions are Isosmotic. Isotonicity: if two solutions are separated by a biological membrane and remain in osmotic equilibrium, the solutions are isotonic with respect to the biological membrane. Biological membranes ≠ perfect semi-permeable membranes

Answer 9

1. Isosmotic solution with blood will only be isotonic if blood cells are impermeable to solute molecules & permeable to the solvent. 2. Osmoticity: property of a solution & is independent of any membrane 3. Tonicity: property of a solution in reference to a particular membrane. 4. Isosmotic solutions of new drugs have to be tested for isotonicity & haemolytic activity. 5. Isosmotic solutions of ammonium chloride, urea also cause haemolysis, i.e. they are not isotonic biological membranes.

Answer 10

For a biological membrane Only if the membrane is impermeable to the solutes then: Isotonic πsolution = πintracellular Hypertonic πsolution > πintracellular Hypotonic πsolution < πintracellular

Answer 11

1. Degree of deviation from tonicity 2. Location of the injection 3. Volume injected 4. Speed of the injection 5. Location, vol & speed determine rapidity of dilution & diffusion

Answer 12

1. Isotonic solutions are preferred 2. Hypotonic solutions adjusted with dextrose or NaCl 3. Hypertonic solutions can’t be adjusted: large vein or slow delivery of small volume required

Answer 13

Excessive hypotonic solutions infusion: RBC swelling, haemolysis, water enter cells & tissues, eventually water intoxication (convulsion, oedema)

Answer 14

Excessive isotonic solutions infusion: possible increase in extracellular fluid volume & circulatory overload

Answer 15

Excessive hypertonic solutions infusion: numerous possible complications, e.g. rapid high % dextrose causes water & electrolyte loss, dehydration & coma

Answer 16

Intraspinal / Intrathecal Injections 1. CSF has small volume & low circulation 2. Injections must be isotonic

Answer 17

Intradermal Injections 1. For diagnostic purposes (allergies). 2. Use isotonic solutions to avoid false signs of irritation

Answer 18

Intramuscular & subcutaneous injections 1. Isotonicity preferred for comfort. 2. Hypertonic solutions may increase absorption of IM drugs as water may be drawn from tissues, increasing dissolution, ergo absorption.

Answer 19

1. TPN = Total Parenteral Nutrition 2. IV infusion of a nutritionally complete formula e.g. amino acids, electrolytes 3. Very high osmolarities, max 60 % dextrose 4. Isotonicity required for Non-IV drug delivery for sensitive mucous membranes

Answer 20

1. Calculate osmolarity generated by components of formulation 2. Determine remaining osmolarity required to make solution isotonic with body fluids 3. Calculate amount of adjusting substance (e.g., NaCl, dextrose) required to make up the shortfall

Answer 21

Osmotic pressure isn’t easily measured, so freezing point depression can be used instead Body fluids have a freezing point of -0.52 ºC (ΔTf = 0.52) The freezing point of 0.9 % NaCl solution is also -0.52 ºC and 0.9 % NaCl is considered isotonic with body fluids. i = van’t Hoff factor Kf = freezing point depression constant (independent of solute), 1.86 for water m = molality (i x m = osmolality) ΔTf = i Kf m Colligative properties are additive, they only depend on the number of “particles” of solute in solution, not their identity Aim: Overall ΔTf from all components of formulation = 0.52 ºC Change in Tf=iKfm

Answer 22

ΔTf (required) = 0.52 – ΔTf (components) Tables provide experimentally-determined ΔTf values for different [of] drugs & excipients As the ΔTf is a colligative property, the relationship with % is usually linear at [low]

Answer 23

NaCl equivalent (ENaCl) of a solute = mass of NaCl that lowers freezing point of a solvent (water) to the same extent as 1 g of the solute Experimentally-determined ENaCl values for drugs & excipients can be found in tables A 2 % solution of acetylcysteine has ENaCl = 0.20 2% = 2 g in 100 ml, so this is equivalent to 2 x 0.2 = 0.4 g of NaCl i.e., 0.4 % NaCl

Answer 24

1. Consider the body to be made of one or more compartments (tanks) 2. A compartment is a body volume: group of tissues &/or fluids, with similar properties 3. A drug is uniformly distributed in a compartment 4. Treatment of data uses first- & zero-order processes of entry into & exit from the compartment

Answer 25

1. The simplest model 2. The most frequently used despite is simplifications & assumptions. 3. The drug is assumed to rapidly distribute into a homogeneous fluid volume in the body

Answer 26

In reality, drug distribution (equilibration between plasma & tissues) requires time. Time required based on: 1. Tissue perfusion & permeability 2. Drug partitioning between blood & tissue or affinity drug-tissue. Distribution kinetics only ignored if acceptable error produced: 1. Satisfactory description of experimental observations 2. No risk in dose calculations.

Answer 27

1. When injected in IV bolus, [] declines exponentially with time, 1st order elimination. 2. Represent Log[] vs time to produce a straight line. 3. C=Co x e power pf –kt 4. InC=iNCo- kt

Answer 28

1. Thiopental: small highly lipid soluble, easily access tissue. Distribution is perfusion rate limited. 2. Semi log[] vs time 3. Drug profile in liver & plasma synchronized, higher [in] plasma 4. Muscle [increases] 1st phase but synchronizes with plasma. Occurs because muscle accumulates drug until its affinity has been satisfied. 5. Drug highly lipid soluble, ergo high lipid affinity, ergo more time needed to satisfy partition coefficient between fat & plasma. 6. Initial phase where [plasma] declines due to elimination & distribution. 7. Once organs reach leaving distribution with plasma, the [declines] parallel to plasma. 8. When the [plasma] is dropping, it drops in other organs, dependent on affinity for the drug.

Answer 29

1. Equilibrium of distribution is fast (~ 5 min) for highly perfused organs (e.g. liver, brain & kidneys = receive a lot of blood) 2. Equilibrium plasma-muscle is achieved in half hour, less blood received. 3. Equilibrium plasma-fat is not achieved in 3.5 hours. 4. Only 20% of drug is eliminated in first 3 hours because the drug is highly lipid soluble, so more time is required to reach [the]. 5. Decline in [plasma] occurs mainly due to the drug distribution to fat and muscle. 6. Adipose tissue: poor perfusion & high partitioning (Pthiopental, fat/plasma= 10) the greater the partitioning of a drug into a tissue: the longer to achieve equilibrium. 7. After enough time the adipose compartment = 40% of V for thiopental 8. Even at equilibrium [thiopental] is NOT the same in all tissues.

Answer 30

Two compartment model Assumptions: 1. Elimination & absorption occur only from center 1st compartment 2. Normally because liver or kidneys will be 1st compartment. 3. Distribution is fast in 1st (plasma, liver, tissues) 4. 2nd compartment includes deeper tissues or tissues with large affinity for the drug, ergo more time to distribute drug. 5. Assume homogenous distribution in 1st compartment, & equilibrium in 2nd 6. Gives complete equilibrium distribution in body.

Answer 31

1. [Plasma] vs time 2. Log conc against time to identify compartment. 3. 1 Compartment is straight line 4. 2 Compartment is curved with an alpha & a beta phase, which decline [in] at different rates due to elimination occurring on the second phase.

Answer 32

The decline in plasma levels is primarily determined by distribution of the drugs to the tissues & elimination.

Answer 33

1. The decline in plasma levels is primarily due to loss of drug from the body. Re-distribution occurs. 2. Equilibrium plasma-tissues is achieved. 3. The body “acts” as a “single container”. 4. The [drug] in plasma & tissues may be different.

Answer 34

1. Following PO administration, can recognize the biphasic curve (slow distribution kinetics) if the absorption process is faster than the distribution. 2. 2 compartment – IV has alpha & beta phase 3. If a drug takes long to reach the Cmax, the alpha phase may not be visible

Answer 35

Two compartment: 1. Central – Amount X1, Volume V1 2. Peripheral – Amount X2, V2 3. Assume first order & linear kinetics 4. K1 controls transfer from 1 to 2 5. K2 controls transfer from 2 to 1 6. K10 – elimination rate constant (sum of Km, metabolism & Ke, excretion)

Answer 36

Alpha phase 1. C1 = A x e power –(alpha x time) + B x e power -(Beta x time) 2. X2= ((K1 x dose)/alpha-beta) x (e power – Betaxt – e power – Alphaxt)

Answer 37

Beta phase 1. C1=Bxe power -(Betaxt) 2. X2 = ((K1 x dose)/alpha-beta) x (e power – Betaxt)

Answer 38

1. k10: constant of elimination rate of drug from central compartment 2. Eszett : “hybrid” constant rate describing how the [drug] declines in plasma during the terminal (elimination) phase. 3. Eszett & t1/2(Eszett) = 0.693/ usual value: because they are more “useful”.

Answer 39

1. V = amount of drug in body/[plasma] 2. Amount in body decreases with elimination 3. [Plasma] decreases with elimination & distribution 4. As distribution occurs, volume of distribution increases until equilibrium of distribution is attained

Answer 40

1. t0 amount of drug = dose 2. At t0 [central compartment] will be: 3. C1t=0 = A+B = Axe –power(-alphax0) + Bxe- power (Betax0) 4. Ergo initial V1 is: 5. V1=amount0/C1t=0 = Dose/A+B 6. V1 useful to relate amount of drug in body with [plasma] after administration

Answer 41

1. In steady state: k1xX1=k2xX2 2. Vss=V1(1+ k1/k2) 3. If K1>K2 then drug has tendency to leave central compartment & go to tissue, making larger volume of distribution. 4. If K1

Answer 42

1. Often used because estimating Vss is not always possible. 2. Defined as: Vbeta=A/C1=Cl/Beta 3. VEszett reminds of V = Cl/k in the one-compartment model

Answer 43

1. Loading dose = [plasma] required x Volume of distribution 2. But which volume: V1 , Vss or VEszett? Consider: 3. V1 < Vss & V1 < V 4. A loading dose estimated with V will be smaller than a loading dose estimated with either Vss or VEszett 5. Dose initially distribute only to V1, & later to Vss or VEszett once equilibrium of distribution is attained. So, [the] reached in plasma (central compartment) will differ.

Answer 44

1. Loading dose based on either Vss or V will exceed target Cp initially & produce toxicity in central compartment 2. Loading dose based on V1 hits target initially but declines rapidly as heart is 1st compartment 3. Target & toxicity in Central compartment 4. Use V1 to attain Cp initially required at target & avoid toxicity 5. Inject dose over 2-3 min to avoid toxicity. 6. Keep efficacy with subsequent doses.

Answer 45

1. Loading dose based on Vss or V will not cause toxicity in 2nd compartment but is sufficient for response 2. Loading dose based on V1 won’t be sufficient for efficacy at target site 3. Target & toxicity in Tissue compartment 4. Use Vss (or V) so once the equilibrium of distribution is attained [the] will be sufficient for efficacy in the heart 5. To avoid toxicity, loading dose is split & given periodically

Answer 46

1. Model independent: AUCInf0-Dose/Cl 2. One compartment model: AUCInf0=C0/k 3. Two compartment model: AUCInf0=A/alpha+B/beta

Answer 47

1. Action: Cardiac glycoside, binds with high affinity & specificity at site on Na+, K+ - ATPase complex. 2. Related to distribution & activity of enzyme Na+, K+ - ATPase. 3. Obesity doesn’t alter distribution, doesn’t distribute to fat 4. Physical exercise decreases [serum] 5. Monitoring 8 hours after dose to ensure equilibrium of distribution

Answer 48

1. Choice of drug 2. Choice of dosage form 3. Design of a dosage regimen

Answer 49

1. Patient 2. Disease characteristics 3. Pharmacokinetics of the drug 4. Individual variations in pharmacokinetics & pharmacodynamics

Answer 50

1. OTC Generally safe & effective for labelled indications. 2. Most drugs are relatively safe & have a broad therapeutic window safety-dose range. 3. The dosage is based on judgement of the physician. 4. No need for a strict individualization of the dose.

Answer 51

1. Some drugs have narrow therapeutic windows (e.g. theophylline, digoxin). 2. Getting right dose regimen difficult due to variability & Nonlinear pharmacokinetics in the therapeutic range 3. Must ensure safe dose regime or plasma level which: - Don’t exceed the minimum [toxic] - Don’t fall below the minimum [effective] 4. For these drugs we will require: - individualization of the dosage regimen - therapeutic drug monitoring (TDM)

Answer 52

1. Therapeutic Drug Monitoring tries to improve patient response &/or decrease adverse reactions 2. Intervention to optimise patient’s outcome by managing medication regimen with the assistance of measured [drug]

Answer 53

1. Drug measuring: determine [drug] in blood sample & relate it to the relevant therapeutic range 2. Main assumption: known relationship between [plasma], therapeutic & adverse effects

Answer 54

Therapeutic window: Approximate average safe & efficient [plasma]. NOT absolute values.

Answer 55

1.Patient information 2.PK model 3.Average population 4.PK parameters 5.Dosage form 5 Determine expected drug [plasma] A) If not met may be issue in compliance, or patient variability. B) If met, can predict PK for dose adjustment.

Answer 56

1. a narrow therapeutic range (effective level close to toxic level) 2. assessment of adherence to medication regimen 3. toxicity suspected – [toxic] 4. lack of response – [sub-therapeutic] 5. unpredictable dose: response relationship 6. no clear observable endpoint to therapeutic success; when a satisfactory response is achieved 7. C at steady-state 8. assess therapy following a change in dosage regimen 9. change in clinical or physiological state of the patient 10 potential DDI due to change in co-medication 11. Similar symptoms of toxicity & disease

Answer 57

1. Patient compliance & Pharmacokinetic variability will affect ADME of drug. 2. ADME, alongside Pharmacodynamic variability, affects the receptor interactions & responses, 3. The receptors will alter the clinical & adverse effects of the drug

Answer 58

1. Low compliance/adherence is a complex problem e.g. chronic illness 2. Key determinant of outcome in medical care 3. Financial burden on health systems 4. Measured by direct (TDM) & un-direct measures

Answer 59

1. Gentamicin C1, C1A & C2 2. Very water soluble 3. poorly lipid soluble 4. poor oral absorption (high MW, very polar)

Answer 60

PAE (Postantibiotic effect): persistent suppression of bacterial growth after exposure of a microorganism to an antibiotic.

Answer 61

1. bactericidal action of aminoglycosides is biphasic. 2. primary phase: rapid, [drug] dependent action (killing-rate directly related to initial [drug]; Cp exceed 10 times the MIC for a given bacteria, more effective than just above MIC). 3. second phase: slow, independent of [drug]; PAE prolonged; surviving bacteria won’t metabolise up to 8 hours after extracellular aminoglycoside washed away. Exposure of surviving bacteria to 2nd dose of aminoglycoside before recovery from 1st impairs 2nd dose’s bactericidal effect.

Answer 62

1. gentamicin has a narrow therapeutic range 2. activity dependent on peak [serum] 3, may cause nephrotoxicity & ototoxicity by accumulation 4. Peak [drug]>MIC 5. Trough values must be low enough to avoid accumulation

Answer 63

1. Dosage regiment, compliance & PK variability affects ADE. 2. ADE alters receptor interactions & responses. 3. This results in the clinical effects: A) [based] bactericidal activity B) Post-antibiotic response C) Resistance to 1st exposure 4. & the adverse effects: Nephrotoxicity & Ototoxicity

Answer 64

1. Active transport into cells of the inner ear & renal proximal tubule. 2. Related with toxicity: 3. Kidneys: major site of drug deposition (40%) 3. 85% of renal drug in renal cortex; 4. Crenal cortex ~ 100 Cp (active process) 5. Toxicity based on treatment duration due to deposition

Answer 65

1. Similar or improved clinical efficacy 2. Convenience & reduced costs 3. Ototoxicity no significant differences 4. Nephrotoxicity reduced: saturable uptake into the renal cortex 5. Larger dose given less frequently (but same daily doe

Answer 66

1. Transporters important for drugs with poor passive permeability. 2. If drug has good passive permeability, it’s able to move across certain membranes by diffusion. 3. When the drug has poor passive permeability being a substrate of a transporter may be the only way that facilitates the passage across the membrane.

Answer 67

Intestine: how much drug can be absorbed (facilitate/hinder) Kidney: how much drug can be eliminated Brain: Mostly efflux to protect the brain

Answer 68

Key transporters super family examples 1. Location & substrates E.g., OATPB1 (liver), OCT3 (everywhere) 2. Uptake for organic anions by OATP & OAT 3. Small organic cations (e.g. metformin) uptake by OCT1 in the liver & OCT2 in the kidney

Answer 69

Transporter superfamilies: ABC: All efflux transporters e.g. P-gp, MRPs SLC: Uptake: OCT1, OCT2, OAT1, OAT3 Efflux: MATE1, MATE2K

Answer 70

1. Distribution & orientation on membranes: e.g. apical (“luminal side”) or basolateral (“blood” side) in polarized cells 2. Co-expression with metabolic enzymes: e.g., P-gp & CYP3A4 co-expression in liver & GIT 3. Spatial distribution within or along the tissue or organ: e.g., levels of P-gp are higher in ileum than duodenum & jejunum. Drugs more/less exposed to P-gp depending on their: - solubility, more soluble=rapid absorption, less P-gp exposure - Release speed, slower = more P-gp exposure

Answer 71

1. Intestine enterocytes: Reduced oral absorption 2. Liver hepatocytes: Enhanced biliary elimination 3. Proximal tubule cells of the kidney: Enhanced renal excretion 4. Blood-brain barrier: Limits distribution to brain 5. Placenta: Limit distribution to foetus, protection from toxicity by sending back drugs to maternal circulation

Answer 72

1. Km = [drug] where rate of transport is half of Vmax 2. Vmax = max rate of transport in saturated transporters 3. At C < < KM, rate of transport directly proportional to C 4. At C ~ KM, rate of transport not directly proportional to C 5. At C >> KM, transporters are saturated, & rate of transport reaches max & constant value.

Answer 73

1. E.g: Atorvastatin is substrate for OATPs & P-gp & is primarily metabolized by CYP3A4: DDIs when co-administered with transporter &/or metabolism inhibitors. 2. E.g. Loperamide induces respiratory depression when administered with P-gp inhibitor quinidine but not when taken alone. 3. Occurs because when Loperamide enters brain it induces respiratory depression, but P-gp inhibitor reduces efflux rate back into blood from brain.

Answer 74

Transporters can be targets: but not common e.g. Probenecid used: interferes with kidney OAT & inhibits tubular reabsorption of urate, increasing excretion of uric acid & decreasing serum urate levels.

Answer 75

Many drugs are substrates for drug transporters: E.g., metformin (substrate for OCT1, MATEs) : Reduced response to metformin in patients with reduced OCT1 activity due to decreased hepatic uptake but no effect on elimination (metformin primarily renal clearance)

Answer 76

Statins (OATPs). 1. Increased risk of muscle toxicity (myopathy) by statins in patients with reduced hepatic OATP1B1 due to reduced hepatic elimination & increased [systemic] 2. Inhibition of efflux transporters mediating biliary excretion: hepatic accumulation of substrates & risk of cholestasis.

Answer 77

1. Intestinal efflux transporters reduce BA of drugs, including those with good passive permeability. P-gp action pushes drug back into lumen. 2. Intestinal uptake transporters may enable PO of drugs with poor passive permeability (e.g., amoxicillin, L-dopa).3. Uptake transporters usually localized at specific areas of the duodenum, the “absorption window” 4. Drug must be available (released/dissolved) as it transits through the absorption window 5. E.g. BA of DOPA reduced when MR, as parts released after absorption window.

Answer 78

1. GI tract efflux & uptake transporters may become saturated: non-linear effects: 2. AUC & Cmax don’t increase proportionally with dose. F (fraction absorbed) is not constant. 3. E.g.: Amoxicillin, F decreases with dose as uptake transporter become saturated

Answer 79

1. P-gp more localised going down small intestine 2. Drug released in upper duodenum, so more drug is absorbed in immediate released 3. MR release where there are more efflux, so lower BA

Answer 80

1. The [distribution] between blood & brain is dependant on lipophilicity of drugs 2. More lipophilic drugs more easily pass the barrier 3. But the efflux contribution to [drug] in the brain dominates passive processes 4. This results in increasing [drug] in brain difficult

Answer 81

Clrenal = Cl glomerular filtration - Cltubular reabsorption + Cltubular secretion

Answer 82

1. Tubular reabsorption can be passive & may be transporter mediated 2. Active tubular secretion always mediated by transporters 3. Saturation can occur, causing inconsistent Cl renal 4. DDIs may will modify Cl renal

Answer 83

BILIARY excretion: Transporters getting drugs into bile tract may rate-control hepatic clearance HEPATIC metabolism: Transporters getting drugs into hepatocytes may rate-control hepatic clearance

Answer 84

1. Probenecid inhibits active tubular secretion of penicillin at the kidney: increasing half life 2. Fruit juice (apple, grapefruit, orange) inhibits OATP1A2 Interactions linked to P-gp: 3. Inducers: E.g. St John’s wort reduces oral absorption of substrate digoxin: reduced F. 4. Inhibitors: Itraconazole, or ritonavir may increase PO absorption of digoxin & cause toxicity 5. P-gp & CYP3A4 overlap on substrates, inducers & inhibitors: E.g, Rifampin induces both CYP3A4 & P-gp

Answer 85

1. Expression levels modified by extrinsic factors: drugs, environmental chemicals, endogenous ligands (bile salts) 2. Pharmacogenetics: Genetic polymorphisms of transporter genes may affect PK - Substantial impact: hepatic uptake by OATP1B1 E.g., variant OATP1B1 associated with simvastatin induced myopathy - Less strong links: variants of OCT1 related to PK-PD: drug exposure & clinical response to metformin - Inter-individual & ethnic variations 3. Underlying disease: liver disease & oncology 4. Drug Interactions 5. Diet & lifestyle: Grape juice inhibits P-gp & some OATPs, alters PK of cyclosporine & fexofenadine

Answer 86

1. Liver action site & clearance site for most statins 2. OATP1 facilitates hepatic uptake. Potentially low OATP1 activity may: - Decrease cholesterol lowering effect (reduced access to action site) - Increase [plasma] due to reduced hepatic Cl - Increase risk of muscle toxicity (myopathy) 3. OATP1 variability’s effect marked for statins with poor passive permeability, depend more on transporters to access liver e.g. Pravastatin

Answer 87

1. Rapid oral absorption. Absorption decreased due to stomach degradation & hepatic 1st pass effect. 2. Hepatic elimination: mostly biliary excretion 3. Genetic variability - OATP1B1 (major role) & OATP2B1 in hepatic uptake 4. Multiple transporters in biliary excretion (MRP2, MDR1, BCRP)

Answer 88

1. Fluctuation: difference between Cmax & Cmin 2. Accumulation: how [much] in steady state in regard to [first] 3. Differences in interval of administration (tau) can change these, even if all other properties the same.

Answer 89

Amount of drug in body decreases with A=A0xepower-k(tau) A=Dxepower-k(tau) 0.693/half life=k Tau = dose interval

Answer 90

For each interval of administration: 1. A peak (Amax of the interval) is observed just after injection, when the new dose adds to the amount of drug remaining from previous doses. Peak A=Amax x e-power(k x t) Where Amax is peak drug amount for given interval & t is time since administration. Trough Amin=Amax x e-power (k x tau) Where Amax is peak of interval, & tau is time since dose administration

Answer 91

Peaks An,max = (D x (1-e –power(n x k x tau)))/ 1-e –power (k x tau) Interval An,t = An,max x e –power (k x t) Trough An,min=An,max x e –power (k x tau)

Answer 92

Peak Cn,max = (D x (1 – e –power (n x k x tau)))/ (V x (1- e –power (k x tau))) Interval Cn,t – Cn,max x e –power (k x t) Trough Cn,min = Cn. Max x e –power (k x tau)

Answer 93

Peak Css,max = D/(V x (1 – e -power (k x tau))) Interval Css,t = Css,max x e – power ( k x t) Trough Css,min = Css,max x e – power (k x tau)

Answer 94

In the steady-state: 1. The [drugs] at peaks & troughs has stabilized. 2. Each dose administration result in a cycle of “[drug] (& amount) vs. time” profile that is the same for all dosing intervals in the steady-state

Answer 95

1. Before the SS the AUC for the [plasma] vs. time for each dosing interval is different 2. In SS, AUC for [plasma] vs. time for each tau is the same & = 3. AUC at 0 to power tau, at SS = D/Cl

Answer 96

1. The AUC0 power tau during a tau in the SS = the AUC0 following a single administration of the same dose. 2. AUC0 power tau during SS = D/Cl = AUC0 power infinite 3. V=For extravascular administration: 4. AUC0 power tau during SS = F x D/Cl = AUC0 power infinite

Answer 97

In SS: rate in = rate out IV infusion: Cp is essentially constant once the steady-state is achieved Infusion rate=ClxCSS Multiple dosesCycles of Cdrug are identical at all time points following each administered dose Dose/tau = ClxCSS,mean

Answer 98

1. Rate in= Dose/tau = ClxCss = rate out 2. Css = Dose/Clxtau = AUC0 power tau/tau 3. Css in multiple dose regimen is [drug] that multiplied 4. Tau gives value of AUC in ss for dose regimen considered 5. Css is not arithmetic mean of Cmax & Cmin

Answer 99

1. To predict time to attain steady state: 2. nSS (number of doses needed to reach SS) 3. Time to reach SS = nSS x tau 4. e.g. nss=15 for tau=6h 5. 15x6-90hours to reach SS

Answer 100

1. f = fraction of SS attained 2. f = Cn,max/Css,max = (D(1-e –power nxkxtau)/V(1-e-power nxkxr))/(D/V(1-e –power kxtau)) 3. f = 1-e –power (n x k x tau) 4. e.g. f for dose n = 0.75, so peak for n is 0.75 in steady state 5. nf = -In(1-f)/kxtau 6. n (number of doses) to reach f depends on: a) Elimination half-life or rate constant of the drug (vol of distribution & Cl) b) tau

Answer 101

1. Once nf known, tf (time to reach f): 2. tf = nf x tau 3. tf = -In(1-f)/kxtau 4. tf depends on elimination t1/2 or k.

Answer 102

1. 95% of SS used as 100% not attainable 2. Time to reach 95% SS in multiple dose regimen = 4.32 x t1/2

Answer 103

1. Fluctuations: oscillations between peaks & troughs at SS 2. Css,max – Css,min = D/V = Cmax n=1 3. Fluctuation = [initial] from dose C0 4. Applies to IV Bolus & extravascular multiple dose regimen

Answer 104

1. Accumulation: relation between tau & rate of elimination 2. When tau is long relative to time to eliminate each dose (reflects t1/2), accumulation is low 3. When tau is short relative to time to elim each dose, accumulation is high 4. Accumulation ratio (R), or extent of accumulation for dose regimen: 5. R = Css,max/Cn=1,max = Css,min/Cn=1,min 6. R = 1/(1- e-power kxtau)

Answer 105

What can be modified: 1. Dose 2. Interval of administration Modified in some populations: 1. Clearance 2. Volume of distribution 3. Elimination t½ & k

Answer 106

1. Use desired Css & Cl to estimate rate of administration 2. Rate in = Dose/tau = Cl x Css = rate out e.g. Rate of admin required to reach [plasma] 20mg/L-1 when Cl=0.32L/h 20mg/L x 0.32L/h = 6.4mg/h

Answer 107

1. Once daily ideal, but if t1/2 <3h either: - Short tau or use IV infusion not bolus - Large dose if therapeutic index is large. e.g. Penicillin t1/2 30min, but given 4-6h 2. When t1/2 = 3-8h e.g. ibuprofen, give 6-8hours 3. When t1/2 = 8-24h, give every t1/2 4. When t1/2 >24h, give OD, or once weekly

Answer 108

1. Css,max = D/(V x (1-e –power k x tau)) 2. Css,min = D/(V x (1-e –power k x tau)) x (e –power k x tau) 3. Tau = -1/k x In(Css,min/Css,max) 4. In(Css,min/Css,max)= -ktau

Answer 109

1. Css,max Css,max = (FxD)/V x (1/(1-e-power kxtau)) x e –power k x tmax 2. Predict Tmax Tmax = (1/ka-k) x In(ka(1-e-power k x tau)/k(1-e-power ka x tau) 3. Predict CCss,min Css,min = (FxDxka/V(ka-k)) x (1/(1-e-power k x tau)) x e – power k x tau 4. [Mean] in SS Css = FxD/ClxTau

Answer 110

1. DL (loading dose) used to raise [plasma] to attain target [drug] faster 2. Convenient for drugs with long t1/2 3. IV Bolus: DL/DM = 1/(1-e –power k x tau) 4. Extravascular: DL/DM = 1/((1-e –power k x tau)x(1-e –power k x tau))

Answer 111

DDIs: When two or more drugs used together, the outcome (efficacy, safety) of the therapy is not necessarily the sum of the effects obtained with the individual use of the drugs at the same dose. This occurs because one drug may modify the PD/PK of another which is known as a Drug-Drug Interaction

Answer 112

Food-Drug interactions (FDIs): Alterations of the pharmacokinetics or pharmacodynamics of a drug resulting from the presence of food and beverages in the gastrointestinal tract or due to effects caused by components of the diet.

Answer 113

Herbal and natural products DIs: Alterations of pharmacokinetics or pharmacodynamics of a drug resulting from the components of herbal medicines

Answer 114

Pharmacodynamic interactions: drugs (chemicals) competing at the pharmacological target or that have similar or opposing PD therapeutic or adverse effects. Mediated by many mechanisms & need to be considered on case-by-case basis.

Answer 115

Pharmacokinetic interactions: ADME modifications leading to changes in PK parameters. “Victim” drug is that one affected by the DI “Perpetrator” drug is the one affecting the PK of the “victim” DIs can affect metabolites

Answer 116

1. cause variability in outcomes of therapy 2. decreased, even eliminate, the efficacy of a treatment 3. cause serious & even fatal adverse events 4. increase hospital admissions 5. increase healthcare costs 6. lead to drugs withdrawal from the market due to DIs discovered post-marketing. 7. Increasing dependant aging population

Answer 117

1. PO absorption & systemic BA of a drug is altered due to another drug, excipients, GI content or changes in GI function. 2. Interactions between drugs or components, e.g., excipients in GIT altering drugs' solubility 3. Indirect effects through alteration of Gl transit, secretions, or hepatic first pass effect. 4. PK parameters typically modified: Rate of absorption: tmax, Cmax, kabsorption Extent of absorption: F, AUC, Cmax

Answer 118

Physicochemical interactions: 1. Complexation of the drug with opposite-charged ion species or to nonspecific adsorption of the drug. 2. e.g.: Metal ions: Tetracycline antibiotics form complexes with metal ions which are poorly absorbed & cephalosporin cefdinir

Answer 119

Alterations of GI pH: 1. Importance depends on physio-chemical (pKa, pH-stability profile, pH-solubility profile) & permeability properties of each specific drug. e.g. 2. H2-antagonists may modify BA of a drug released from a formulation through a pH-dependent mechanism. 3. Enoxacin (antibiotic) has a pH-dependent aq solubility, which can limit absorption.

Answer 120

Alterations of GI Motility: 1. Drugs primarily absorbed from intestine, so alterations in gastric emptying rate & small intestinal transit time can alter rate & extent of absorption. 2. Specific effects will depend on the physio-chemical & permeability properties of each specific drug. 3. E.g. motility decrease may cause increased absorption due to prolonged dissolution time & increased contact time in intestine, e.g. paracetamol

Answer 121

Food – drug interactions: 1. Effects of food on physiology: stomach emptying rate, intestinal motility, splanchnic blood flow, bile secretion, acid secretion, enzyme secretion, active absorption. 2. e.g. longer gastric retention, increased degradation, possible interface with active transport 3. Direct effects of food: Enoxacin (antibiotic) has a pH-dependent aqueous solubility.

Answer 122

Protein binding displacement interactions. 1. Drugs can be displaced by: other drugs, endogenous compounds, [the] possibly altered in disease. 2. Higher risk for highly bound drugs with narrow therapeutic window

Answer 123

Modulation (inhibition & induction) of active (uptake & efflux) transporters 1. can alters drug distribution to tissue relevant for efficacy or toxicity 2. Less known & more complex to characterize 3. e.g. Requiring imaging techniques to assess distribution

Answer 124

1. e.g. IV administration of sulphonamides to neonates displaces plasma-bound bilirubin, which enters the CSF, resulting in kernicterus.

Answer 125

1. Parenteral administration of the displaced drug which has a high extraction ratio: 2. Accumulation of drug may occur as the Cl not modified

Answer 126

1. Normally total (ClT) is measured, & the “usual” free fraction is used to estimate Cfree to make dosing recommendations. 2. If free fraction is modified, & this is unknown, the recommendation might be wrong.

Answer 127

1. Excretion & metabolic interactions possible 2. e.g., excretion/metabolism of a drug (or its metabolites) is modified by another chemical (drug, & components of diet & herbal/natural products) 3. DIs at enzyme (e.g. CYP) & transporter (e.g. P-gp) levels

Answer 128

1. CYP 3A represents major contribution to first past effects 2. CYP 3A is involved in oxidative metabolism of half of therapeutic drugs 3. Several isoforms: CYP3A4, CYP3A5, CYP3A7 (foetal) 4. CYP 3A variability: Marked inter- & intra- variability in metabolizing activity, regulation & interactions

Answer 129

1. Cranberry juice: use to reduce recurrence of UTIs 2. Suspected perpetrator in cases of excessive warfarin anticoagulation 3. Potential impact on clinical trials / real world data 4. Strict labelling: i.e., “avoidance advice” given variable content of diet & herbal products

Answer 130

1. PK parameters (V ,Cl, , AUC) of drug in healthy/monotherapy, & a change with respect to standard therapy or patient population: 2. Drug interactions: a) metabolism induction & inhibition (Clint) b) protein binding – altered free fraction ()

Answer 131

1. Hepatic disease: Decreased hepatocellular activity (Clint) 2. Disease modified hepatic blood flow (Q) 3. Predict impact of the “change” on the PK of the drug by: a) determining if the drug has a high or a low EH b) uses simple model to predict modifications in the PK of the drug & suggest potential dose adjustments

Answer 132

Hepatic clearance (ClH) measures drug loss across liver by metabolism & excretion & defined as either: a) Ratio between hepatic elimination rate & the incoming [drug] b) Volume of blood entering liver from which all the drug is removed per unit time.

Answer 133

1. e.g.; if ClH = 60L/h & QH = 90 L/h 2. Every hour the liver can extract all drug in 60L of blood. 3. In this example, 2/3 (60/90) of the drug present in the blood entering the liver every hour is cleared & 1/3 (30/90) is not eliminated. 4. So, the EH = 60L/90L = 0.66

Answer 134

1. Hepatic Extraction Ratio: the fraction of a drug eliminated passing through the liver 2. Eh =(Cin-Cout)/Cin =1-(Cout/Cin) 3. Thus, the value of EH can range from: 0 = (no drug eliminated) to 1 (all the drug is eliminated) 4. If EH = 0.25 means 25% of the drug entering the liver is eliminated.

Answer 135

Hepatic clearance of a drug will be determined by: 1. Rate of drug presentation (its delivery) to the liver, which is determined by hepatic blood flow (QH) 2. Efficiency of drug removal by liver, or fraction of drug presented to the liver which is eliminated by this organ, given by EH 3. ClH = QH x EH

Answer 136

Hepatic blood flow (QH) determines drug presentation to the liver Free fraction () the unbound fraction of the drug can enter hepatocytes where metabolism takes place.

Answer 137

1. Intrinsic Clearance (Clint) liver’s ability to eliminate the drug in the absence of restrictions imposed by protein binding & drug delivery to the liver by blood flow, in other words: 2. the (hypothetical) value of ClH if QH (hepatic blood flow) was unlimited & all the drug is unbound ( = 1) 3. Clint represents how efficient liver enzymes are in metabolizing a given drug. It “can be approximated” to: Clint = Vmax/KM 4. Clint depends on the amount of enzyme present and the affinity of a drug for the enzyme 5. The liver cannot metabolize a drug faster than it is presented by the blood, so ClH is usually lower than Clint. 6. Inducers increase Clint & inhibitors decrease Clint

Answer 138

For some drugs the time required for: 1. leaving blood cells 2. dissociating from plasma proteins, 3. diffusing hepatic membranes 4. being metabolized by enzymes 5. being transported to bile is so short that most of the drug being delivered by the blood is removed by the liver. Reach ClH similar to HQ

Answer 139

Other drugs have low EH due to: 1. slow dissociation from RBC 2. slow dissociation from plasma proteins 3. slow diffusion into the hepatocytes 4. slow enzymatic reaction 5. slow transport into the bile. Means they have low ClH

Answer 140

DDIs: When multiple drugs used together, the outcome (efficacy, safety) of the therapy is not necessarily the sum of the effects obtained with the individual use of the drugs at the same dose. Occurs because one drug may modify the PD/PK of another which is known as a Drug-Drug Interaction

Answer 141

Food-Drug interactions (FDIs): Alterations of the PK or PD of a drug resulting from the presence of food & beverages in the GIT or due to effects caused by components of the diet.

Answer 142

Herbal & natural products DIs: Alterations of PK or PD of a drug resulting from the components of herbal medicines

Answer 143

PD interactions: drugs (chemicals) competing at the pharmacological target or that have similar or opposing PD therapeutic or adverse effects. Mediated by many mechanisms & need to be considered on case-by-case basis.

Answer 144

PK interactions: ADME modifications leading to changes in PK parameters. “Victim” drug is that one affected by the DI “Perpetrator” drug is the one affecting the PK of the “victim” DIs can affect metabolites

Answer 145

1. cause variability in outcomes of therapy 2. decreased, even eliminate, the efficacy of a treatment 3. cause serious & even fatal adverse events 4. increase hospital admissions 5. increase healthcare costs 6. lead to drugs withdrawal from the market due to DIs discovered post-marketing.

Answer 146

1. Increasing problem due to polypharmacy in aging population 2. Elderly patients tend to use more medication than younger 3. Loss of “reserve function” with age. The same DI may result in more severe consequences than in younger population.

Answer 147

1. routinely assessed through clinical development 2. part of the regulatory dossier and considered in the benefit-risk assessment 3. included in labelling information 4. Further investigated in post-approval studies on DIs, to optimize safety & treatment recommendations

Answer 148

1. PO absorption & systemic BA altered due to another drug, excipients, GI content or changes in GI function. 2. Interactions between drugs or components, e.g., excipients in GIT altering drugs' solubility 3. Indirect effects through alteration of Gl transit, secretions, or hepatic first pass effect. 4. PK parameters typically modified: Rate of absorption: tmax, Cmax, kabsorption Extent of absorption: F, AUC, Cmax

Answer 149

complexation of the drug with opposite-charged ion species or to nonspecific adsorption of the drug. e.g.: Metal ions: Tetracycline antibiotics form complexes with metal ions which are poorly absorbed & cephalosporin cefdinir

Answer 150

Alterations of GI pH: Importance depends on physico-chemical (pKa, pH-stability profile, pH-solubility profile) & permeability properties of each specific drug. e.g. a) H2-antagonists may modify BA of a drug released from a formulation through a pH-dependent mechanism. b) Enoxacin (antibiotic) has a pH-dependent aq solubility, which can limit absorption

Answer 151

1. Drugs primarily absorbed from intestine, so alterations in gastric emptying rate & small intestinal transit time can have important effects on rate & extent of absorption. 2. Specific effects depend on physico-chemical & permeability properties of each specific drug. 3. E.g. motility decrease may cause increased absorption due to prolonged dissolution time & increased contact time in intestine, e.g. paracetamol

Answer 152

1. Effects of food on physiology: stomach emptying rate, intestinal motility, splanchnic blood flow, bile secretion, acid secretion, enzyme secretion, active absorption. 2. e.g. longer gastric retention, increased degradation, possible interface with active transport 3. Direct effects of food: Enoxacin (antibiotic) has a pH-dependent aqueous solubility.

Answer 153

1. Drugs can be displaced by: other drugs, endogenous compounds, [the] possibly altered in disease. 2. Higher risk for highly bound drugs with narrow therapeutic window

Answer 154

1. can alter drug distribution to tissue relevant for efficacy or toxicity 2. Less known & more complex to characterize 3. e.g. Requiring imaging techniques to assess distribution

Answer 155

1. Rapidly administered displacement agent: e.g.: IV administration of sulphonamides to neonates displaces plasma-bound bilirubin, which enters the CSF, resulting in kernicterus. 2. Parenteral administration of the displaced drug which has a high extraction ratio: Accumulation of drug may occur as the Cl not modified 3. Therapeutic drug monitoring. Normally total (ClT) is measured, & the “usual” free fraction is used to estimate Cfree to make dosing recommendations. If free fraction is modified, & this is unknown, the recommendation might be wrong.

Answer 156

1. Excretion & metabolic interactions possible 2. e.g., excretion/metabolism of a drug (or its metabolites) is modified by another chemical (drug, & components of diet & herbal/natural products) 3. DIs at enzyme (e.g. CYP) & transporter (e.g. P-gp) levels

Answer 157

1. CYP 3A represents major contribution to first past effects 2. CYP 3A is involved in oxidative metabolism of half of therapeutic drugs 3. Several isoforms: CYP3A4, CYP3A5, CYP3A7 (foetal) 4. CYP 3A variability: Marked inter- & intra- variability in metabolizing activity, regulation & interactions

Answer 158

1. St John’s Wort: dietary supplement Chronic uptake induces CYP3A, greater effect in small intestine than liver Transient (2 weeks) increased expression of intestinal P-gp Has caused low levels of indinavir & cyclosporine (resulting in rejection) 2. Grapefruit juice: Inhibits intestinal CYP3A, P-gp & OATP Variable effects: individual CYP3A baseline & timing 3. Cranberry juice: use to reduce recurrence of UTIs Suspected perpetrator in cases of excessive warfarin anticoagulation 4. Potential impact on clinical trials / real world data 5. Strict labelling: i.e., “avoidance advice” given variable content of diet & herbal products

Answer 159

e.g.: Absorption interaction at transporters level that can be observed depending on how close consumption of perpetrator & victim was. 1. Fexofenadine (victim) + grapefruit juice (inhibits OATP1A2 – intestinal uptake): 2. Grapefruit can decrease absorption of fexofenadine 3. Max effect when grapefruit juice taken with fexofenadine. 4. No effect if 4 hours apart 5. Fexofenadine primarily renally excreted, interaction occurs at the absorption level.

Answer 160

- metabolism induction & inhibition (Clint) - protein binding – altered free fraction (alpha) - Hepatic disease: Decreased hepatocellular activity (Clint) - Disease modified hepatic blood flow (Q)

Answer 161

1. determining if the drug has a high or a low EH 2. uses simple model to predict modifications in the PK of the drug & suggest potential dose adjustments

Answer 162

Hepatic clearance (ClH) measures drug loss across liver by metabolism & excretion & defined as either: - Ratio between hepatic elimination rate & the incoming [drug] - Volume of blood entering liver from which all the drug is removed per unit time. e.g.; if ClH = 60L/h & QH = 90 L/h Every hour the liver can extract all drug in 60L of blood. In this example, 2/3 (60/90) of the drug present in the blood entering the liver every hour is cleared & 1/3 (30/90) is not eliminated. So, the EH = 60L/90L = 0.66

Answer 163

Hepatic Extraction Ratio: the fraction of a drug eliminated passing through the liver Eh =(Cin-Cout)/Cin =1-(Cout/Cin) Thus, the value of EH can range from: 0 = (no drug eliminated) to 1 (all the drug is eliminated) If EH = 0.25 -> 25% of the drug entering the liver is eliminated.

Answer 164

1. Rate of drug presentation (its delivery) to the liver, which is determined by hepatic blood flow (QH) 2. Efficiency of drug removal by liver, or fraction of drug presented to the liver which is eliminated by this organ, given by EH 3. ClH = QH x EH

Answer 165

Hepatic blood flow (QH) determines drug presentation to the liver Free fraction () the unbound fraction of the drug can enter hepatocytes where metabolism takes place. 1. Intrinsic Clearance (Clint) liver’s ability to eliminate the drug in the absence of restrictions imposed by protein binding & drug delivery to the liver by blood flow, in other words: 2. the (hypothetical) value of ClH if QH (hepatic blood flow) was unlimited & all the drug is unbound ( = 1) 3. Clint represents how efficient liver enzymes are in metabolizing a given drug. It “can be approximated” to: Clint = Vmax/KM 4. Clint depends on the amount of enzyme present and the affinity of a drug for the enzyme 5. The liver cannot metabolize a drug faster than it is presented by the blood, so ClH is usually lower than Clint. 6. Inducers increase Clint & inhibitors decrease Clint

Answer 166

EH or liver capacity to extract irreversibly these drugs is very high (>0.7) and approaches 1 ClH = QH x E

Answer 167

These drugs have high EH For some drugs the time required for: 1. leaving blood cells 2. dissociating from plasma proteins, 3. diffusing hepatic membranes 4. being metabolized by enzymes 5. being transported to bile ClH is so short that most of the drug being delivered by the blood is removed by the liver.

Answer 168

Other drugs have low EH due to: 1. slow dissociation from RBC 2. slow dissociation from plasma proteins 3. slow diffusion into the hepatocytes 4. slow enzymatic reaction 5. slow transport into the bile.

Answer 169

1. ClH depends on rate of drug presentation to the organ by the blood; it is “perfusion” rate-limited.Hepatic Clearance approaches hepatic blood flow (QH ≈ 1.5 L/min or 90 L/h) 2. Hepatic Clearance is: very sensitive to changes in blood flow relatively insensitive to changes in plasma binding, cell metabolizing activity (inducers, inhibitors) 3. Usually, drugs with high EH have low oral BA because they are metabolized extensively by hepatic First Pass effect Fhepatic first-pass = 1- EH

Answer 170

1. One of these processes rate limits ClH: Partition from blood cells, dissociation from plasma proteins, slow passage through membranes & into bile.Usually, the drug is a poor substrate for the enzymes 2. Hepatic Clearance is: sensitive to changes plasma binding, cell metabolizing activity Insensitive to changes in blood flow 3. We would predict high oral BA, F~ 1 for drugs with low EH Yet, a drug with low EH may still have poor oral BA, due to other the reasons than hepatic first pass effect

Answer 171

1. Drug interactions with inducers. E.g., Drug A increases rate of synthesis of enzymes involved in Drug B metabolism. E.g. Drug A increases Clint of Drug B 2. Drug interactions with inhibitors: Drug A decreases Clint of Drug B 3. Reduced hepatocellular activity: hepatic disease, dietary deficiencies: Decrease in Clint. 4. Modified hepatic blood flow (increase or decrease QH): disease or surgery. 5. Altered protein binding (increase or decrease alpha) of Drug B due to DIs or altered protein synthesis. proteins, so Drug A displaces Drug B from plasma proteins, so Drug A increases alphaB Outcome & its potential clinical relevance dependant on: 1. Whether the drug involved (the victim in a DDI) has a low or a high extraction ratio in the eliminating organ where the induction occurs 2. Administration route (oral versus iv)

Answer 172

1. “Changes in organ blood flow only affects the clearance of drugs with high extraction ratio (perfusion-rate limitation)” 2. But changes in blood flow can cause other effects e.g. Anoxia decreasing hepatocellular activity, so EH may lower, blood flow changes accompanied with symptoms

Answer 173

1. Free fraction of a drug in plasma (Cfree, plasma) is not the same as the total [drug] (Cplasma). 2. Bound drug, forms a complex with plasma proteins, cannot cross capillary membranes to reach other tissues & organs. 3. Therapeutic & toxic effects more closely related to the free [drug] (Cfree, plasma) rather than the total [drug] (Cplasma). 4. Elimination of drugs occurs through the free drug, not the bound form. 5. Factors such as drug interactions, diseases, or physiological changes can affect the free fraction of a drug in plasma.

Answer 174

Protein binding: Normally characterized by the free fraction or fraction unbound of the drug (alpha, fu). Can be altered by: DIs: drug displaced from protein binding sites by a 2nd drug Disease: changes in protein synthesis or in protein-drug affinity, or due to accumulation of compounds altering normal binding of the drug.

Answer 175

1. Hepatic clearance: Clear effect on the ClH of drugs with low EH which can be predicted by ClH = Clint x alpha. Probably, effect on the ClH of drugs with “mid” (0.3-0.7) EH, but this effect is more difficult to predict. No effect on the ClH of drugs with high EH 2. Renal clearance: Model predicts same trends than for hepatic clearance 3. Volume of distribution: Increase in  normally leads to higher V

Answer 176

1. According to the model, in this case: ClH=alpha x Clint: so ClH will be modified with . 2. ClT will be modified depending on the contribution of ClH to ClT Let’s assume a drug with low EH: 3. which is primarily metabolized by the liver, so ClT will be modified with  efficacy (or its toxicity) of which, in a multiple dose regimen is linked to the free concentration of the drug in the steady-state (Cfree,ss) Cfree,ss=a x Css

Answer 177

1. When a drug is given orally, first pass effect can occur both in the liver & the intestinal wall. 2. In fact, CYP3A represents: 30% CYP in liver, 70% CYP in small intestine. 3. CYP3A is involved in many DDIs. 4. Thus, many CYP3A-mediated DDIs effect both liver (Cl and first-pass) & intestinal level (first-pass).

Answer 178

Our model for DIs is “static” however, often the effects of interactions are not immediate, requiring some time for being seen, & to go away once the perpetrator is removed.

Answer 179

1. Rate of elimination = k.A A = amount in the body 2. Rate of absorption = kabs.X X = amount at absorption site 3. Rate of metabolite formation = km.A A = amount in the body 4. 1st order: reaction is entirely dependant on one [reactant’s]

Answer 180

1. Enzymes & transporters may reach max capacity 2. Proteins have fixed number of binding sites 3. This means saturation is possible

Answer 181

1. Saturation of enzymes & transporters occurs at [drug] > [therapeutic range], showing linear (1st order) kinetics, 2. Some drugs’ saturation occurs at therapeutic levels, causing non-linear PK 3. Other reasons for non-linearities: e.g., solubility not based on ADME causes.

Answer 182

Dose-dependent kinetics: 1. One or more PKs parameters change with administration of different doses to the same individual(s). 2. e.g.: F, kabs, V, ClR, ClH, t1/2, k Time-dependent kinetics: 1. One or more PKs parameters change with continuous or repeated administration in the same individual(s). 2. e.g.: F, kabs, V, ClR, ClH, t1/2, k

Answer 183

1. PK parameters (Cl, V, F) of a drug are constant in linear PK - With administration of different doses in the same individuals - Or during continuous or repeated administration. 2. AUC is proportional to the dose in linear PK: i.e.; double the dose, double AUC 3. [Plasma] are proportional to dose given in linear PK 4. In linear PK same [dose-normalized] are observed for different doses of a drug, given same conditions 5. This is because [dose-normalized] only depend on constant linear PK parameters

Answer 184

1. Uptake transporters (into tissue): < absorption occurs, < expected AUC increase with D 2. Efflux transporters (secretion into lumen): > absorption, > expected AUC increase with D 3. Enzymes in enterocytes (intestinal first-pass): > drug absorbed, AUC with D increase > expected 4. Hepatic first-pass enzymes: > drug absorbed, > expected AUC with D

Answer 185

1. Plasma proteins binding: Higher free faction at higher doses, saturation of plasma binding may be clinical for some drugs 2. Uptake transporters (into tissue): doses 3. Efflux transporters (out of brain): >proportional [tissue] at >doses

Answer 186

Saturated Metabolism Hepatic enzymes: >Cl for higher [drug] e.g. higher dose AUC increase > expected with D

Answer 187

Saturated Excretion: Uptake transporters (into kidney or liver): >Cl for higher [drug] e.g. higher dose Efflux transporters (into urine or bile): AUC increase > expected with D

Answer 188

The metabolism of a drug by a saturable enzymatic process can be described using the M-M equation dC/dt = (Vmax x C)/(Km+C)=rate of metabolism Where: Vmax is the maximum elimination rate [mass/time] KM (mass/volume) is the Michaelis constant: [drug] at where rate is half Vmaxis a hybrid rate constant in enzyme kinetics. is NOT an elimination rate constant.

Answer 189

When a drug goes under saturable first pass metabolism 1. Fraction lost by first pass effect might be dose-dependent: - F < for larger doses (F = dose independent in linear PK) 2. Sustained release forms may have lower F than immediate release products of the same drug - A slower [passage through / exposure to] the liver may increase first-pass effect (lower F). - A faster [passage through / exposure to] the liver may decrease first-pass effect (higher F).

Answer 190

1. 3 mechanisms: filtration, reabsorption & tubular secretion contribute to renal excretion 2. ClR = Clfiltration + Clsecretion – Clreabsorption 3. Glomerular filtration & passive reabsorption cannot be saturated & are always linear processes, so Clfiltration & Clpassive reabsorption are constant 4. Active reabsorption & active secretion are can be saturated (transport mediated) 5. If saturation doesn’t occur, transport rate proportional to [drug], Cl secretion & Cl active reabsorption are constant. 6. If saturation of transporters mediating active secretion occurs: 7. Rate of active secretion won’t increase proportionally with [drug] 8. So Clsecretion will decrease as [drug] increase 9. ClR will decrease with [drug] 10. decrease ClR = Clfiltration + decrease Clsecretion – Clreabsorption 11. e.g. can occur to dicloxacillin