Lecture 2: Pharmakokinetics Flashcards
What is pharmakokinetics?
The study of how the body absorbs, distributes, metabolizes, and eliminates (ADME) a drug over time
The application of mathematical formulas to ADME
How drugs move through the body
Primary sites of ADME
Mouth (some absorption)
Stomach (some absorption, 1st pass effect)
Small intestine (primary site of absorption)
Kidney (primary site of excretion)
Liver (primary site of metabolism)
Blood (distribution)
Uses of PK
– Apply PK principles to clinical practice
– Determine rates of ADME, etc.
– Calculate the bioavailability percentage
– Predict plasma (blood) concentrations related to drug dose
– Optimize dose regimens for best efficacy/toxicity
– Assess factors that may alter drug disposition (metabolism)
Clinical goal of PK?
Enhancing efficacy and decreasing toxicity
Interrelationships of ADME
Bound drug is restricted
Interactions between compartments
(see figure)
From dose to effect
See figure
Routes of administration for drug
- Oral
- IV
- Subcutaneous
- Intramuscular
- Transdermal patch
- Rectal
- Inhalation
- Sublingual
See figure
How do drugs cross cell membranes? (essential to move through body)
- passing through channels or pores
- passing through the membrane with the aid of a transport system, or
- penetrating directly
Where are transporters found?
Liver
Kidneys
Intestines
Brain capillaries
What is the most common way that drugs cross the membrane?
Direct penetration
What does the movement through the body depend on for most drugs?
Ability to penetrate membranes directly
Most drugs are too large to pass through channels
Most drugs lack transport systems to help them cross the membrane
What characteristic must a drug have to penetrate cell membranes directly?
Lipid soluble
One-compartment model of drug disposition
Whole body is compartment.
Drugs that do not extensively distribute into extravascular tissues
Not realistic, but is an approximation
See figure
Two compartment model of drug disposition
Drugs that do extensively distribute in tissue
See figure
Key parameters in PK
Bioavailability
Drug Accumulation
Volume of Distribution - Vd
Clearance
Drughalf-life-T1/2
Bioavailability def
the fraction of unchanged drug reaching the systemic circulation following administration by any route
Measures absorption
Drug accumulation def
drug accumulation is inversely proportional to dose lost (elimination)
Volume of distribution (Vd) def
the measure of the apparent space in the body available to contain
the drug – how drug is distributed in body relative to plasma
Clearance def
the measure of the ability of the body to eliminate the drug
Drug half life (T1/2)
the time required to change the amount of drug in the body by one- half during elimination
Inverse relationships of accumulation and elimination
At one half-life, 50% of drug has accumulated/been eliminated
2 half lives, 75% of drug has accumulated, 75% eliminated
5 half lives to reach plateau
See figure
Bioavailability formula
Bioavailability= (AUCadminroute/AUCIV)x100
IV administration is used as a reference
Drug accumulation formula
Accumulation factor = 1 / dose lost (ie, the elimination fraction)
Volume of distribution formula
VD = Amount of drug in body (mg) / Concentration of drug in plasma
(mg/L - quotient expressed in L)
Clearance formula
CL = (0.693 / t 1⁄2 ) x VD
0.693 = natural log constant
Determination of drug absorption
- Timetopeakconcentration - Rate
- Peak concentration - Rate and extent
- Area under the plasma concentration vs time curve (AUC) - Extent
See figure
What does the area indicate on a plasma concentration vs time graph
Area reflects extent of absorption of drug
Area reflects actual body exposure to drug
See figure
Routes of administration and bioavailability
Decreasing bioavailability: IV, transdermal, IM, SC, rectal (PR), Oral (PO), inhalation
See figure
Admin route with most rapid onset
IV
Inhalation, but range of bioavailability is greater
Which admin route is most convenient
Oral
Which admin route has prolonged duration?
Transdermal patch
Limitations of drug absorption
Tissue perfusion (Blood flow)
Diffusion-limited absorption - Partition coefficient (a measure of the difference in solubility of the compound in 2 phases, eg, water/membrane interface)
First pass effect
What is the first pass effect?
Rapid liver inactivation of oral drugs
What is enterohepatic cycling?
Recycling of drug through vessels and organs so that drug can be further utilized. Drug gets another chance to do its job. (kind of like the opposite of the first pass)
Thanks to bile duct
Reduces elimination
Prolongs t1⁄2
Factors influencing drug absorption
Formulation
Watersolubility
Lipidsolubility
pKa
GI motility
Posture
Otherdrugs/foods • GastricpH
What is ion trapping?
an acidic drug will be non-ionized in acid media and ionized in alkaline media.
example: aspirin (an acidic drug) dissolves in stomach (in acidic compartment, pH=1 to 2) and gives up a H+, and then uncharged species passes across membrane to a basic environment (plasma pH=7.4)
Ion trapping of acidic and basic drugs
See figure
Relationship of pH and pKa
pH < pKa: protonated form of drug
pH > pKa: deprotonated form of drug
What is the henderson hasselbach equation?
a relationship between pKa and ratio of acid-base concentrations to pH
What can HH equation be used for?
determining how much drug on each side of membrane
What is pKa?
measure of the strength of the interaction of a drug (compound) with a proton
pH is a measure of hydrogen (H) ion concentration (acids have more H)
Why do drugs pass through membranes in stomach easier uncharged?
The stomach is acidic (pH 1 to 2) and acidic drugs don’t ionize in acid compartments, so drugs pass thru membranes in stomach more easily uncharged
Why do drugs pass through membranes in intestines easier uncharged?
The intestine is more basic (pH sm. int.=8.5, lg. int. =5.5 to 7)and basic drugs don’t ionize in basic mediums, so drugs pass thru membranes in intestine more easily uncharged
Example of acidic drug
Aspririn
How to attain steady state?
AKA therapeutic window
Sweet spot of drug concentration in plasma
Attained by continuous IV infusion
Steady state achieved when rate of drug
elimination equals rate of administration
Boundaries: toxic plasma level, minimum effective plasma level
See figure
Plasma concentration during frequent and infrequent dosing
See figure
What is the most common protein for bound drug?
Albumin
Bound vs unbound drug
Only unbound drug can leave vessels
Bound drugs are too big
A lot of bound drug can alter distribution times
Volume of distribution (need to look up)
the measure of the apparent space in the body available to contain the drug – how drug is distributed in body relative to plasma
= total amount of drug in body/plasma concentration
not a real volume or space, but rather a calculated value used to determine the tissue distribution of a drug
What can you use Vd for?
Needed for determining clearance of a drug from the body
Needed for determining loading dose of a drug
A high Vd means that drug not staying in vascular compartment (ie, extensively distributed)
Vd might actually surpass body fluid vol.
Formula for loading dose
Loading dose = Vd x desired plasma conc
Loading dose vs no loading dose
See figure
Loading dose is higher than maintenance dose
Dosing rate formula
Dosing Rate = CL x TC (or target concentration-plasma)
= (vol / time) (amt / vol) = amt / time
Formula for maintenance dose
Maintenance Dose = (Dosing Rate/F) x Dosing Interval
= (amt / time) (time)
= amount
Where F = fraction absorbed (bioavailability)
Formula for loading dose
Loading Dose = VD x TC (assuming F close to 1)
= (VD x TC ) / F
Factors influencing drug distribution in the body
pKa of compound and pH of tissue compartment
acidic drugs more likely to be concentrated in blood compartment
basic drugs more likely to be concentrated in tissue
Drug binding
Specialized distribution barriers (BBB, placenta)
Drug metabolites vs parent compound
Drug metabolites are usually more polar than their parent compound
Drug metabolizing enzyme expression
Expression differs among tissue type
Phase 1 metabolism reactions
Oxidation, Reduction, hydrolysis
Phase 2 metabolism reactions
Conjugation:
Glucuronidation
Sulfation
Acetylation
Phase 1 and Phase 2 reactions diagram
See figure
Pathways of drug transportation
See figure
Some drugs become more hydrophilic
Some drugs skip phase I
Some drugs become less active or activity changes
First order metabolism
Most drugs 1st order
Rate of drug metabolism proportional to dose
Zero order metabolism
e.g., aspirin, ethanol
Enzyme is saturated
Rate of drug metabolism remains constant over time
First order and zero order reactions diagramX
See figure
Therapeutic Consequences of Phase I and Phase II Metabolism
Accelerated renal excretion
Drug inactivation
Activation of prodrugs
Decreased toxicity (not always true)
Increased therapeutic action
Increased toxicity
How to calculate total clearance
Need to add clearances for all organs together (see figure)
What is the importance of Cl
Provides an index of the efficiency by which a drug is removed from the body
Is subject to changes due to disease state, genetic and environmental factors
Needed for determining Dosing Rate and Maintenance Dose.
Clearance in elderly people
Clearance is slower
slower exrcetion, prolonged action in the body
so we can use a lower dose
Clearance in Relationship to Drug Elimination
Clearance (Cl) – the volume of plasma that would contain the amount of drug excreted per unit time (minutes)
Volume of plasma that would have to lose all of the drug that it contains within a unit of time (usually 1 min) to account for an observed rate of drug elimination
Clearance expresses the rate or efficiency of drug removal from the plasma vol/time (ml/min)
Cl = ke (Vd) or Cl = (0.693/t1/2) * Vd
How many half-lives are required to eliminate a single dose of a drug from the body?
Five half lives
See figures
What is half life?
The time it takes for drug concentration in plasma to decline by 50%
t1/2 = 0.693/ke
What order is most drug PK?
Most drug PK is first order - equal proportion of drug is removed per unit time
Renal elimination of drugs
Low MW drugs enter kidney (via renal artery)
Lipid soluble drugs move back into blood
Non-lipid soluble, polar, and ionized drugs remain in urine
3 steps (glomerular filtration, tubular reasborption, tubular secretion)
See figure
What is used to assess renal impairment?
Creatinine clearance
What does metabolism do to activity of drug?
Metabolism often removes biological activity, but can also result in active drug
What would make a small Vd?
If concentration of drug in plasma is high. For example, if the drug is trapped in the plasma compartment (such as very strong binding to serum albumin) = measured concentration would be high
What would make a high Vd?
If drug is sequestered from the plasma into lipid as a result of the drug being highly lipid soluble.
Concentration in plasma will be low and Vd will go up
What is a pitfall of using Vd?
Does not give an indication of where the drug is anatomically
What are two other factors that affect Vd?
how lipid soluble the drug is and whether it binds to tissue proteins.
Both of these factors increase the drugs volume of distribution because the drug is NOT in the plasma or blood compartment.
Factors that effect Vd and their effect on half life
Ageing (decr muscle) - decr T1/2
Obesity (incr adipose) - incr T1/2
Pathologic fluid - incr T1/2
Factors effecting Cl and their effect on T1/2
Induction of Cyp450 - decr T1/2
Inhibition of Cyp450 - inc T1/2
Organ failure - inc T1/2
Inter-relationship between Half-life, Vd and Clearance
Cl=(0.693/t1/2)*Vd
t1/2 = [(0.693) * Vd] /Cl
Drug transporting proteins
Organic anion transport proteins (OATs or OATPs)
Organic cation transport proteins (OCTs) - New nomenclature - Solute Carrier (SLC) transporters
P-glycoprotein (P-gp or MDRs)
MRP - multidrug resistance-associated proteins
Why is the location of a drug transporter important?
Determines function
Renal drug transporters important for elimination substrates
OCT’s- TEA
OAT’s- alpha KG
Oatp’s- sulfobromophthalein
MDR-verap/CsA/Elacridar
MRP’s- indo
What is the major route for drug elimination for most drugs?
Renal excretion
3 steps of drug excretion
Glomerular filtration
Tubular reabsorption
Tubular secretion
What is a prodrug?
Inactive form of a drug that needs to be activated to have effect
Often activated by metabolism, which increases bioavailability
What are the hepatic drug metabolizing enzymes?
Microsomal enzyme system
aka: P450 system
Families of P450 system
12 families
3 of these families metabolize drugs (CYP1,2,3)
9 of these families metabolize sterioids and fatty acids, etc.
CYP nomenclature
Family: CYP1, 2, 3
Subfamily: added letters
Gene/isoenzyme: added numbers
See figure
Proportion of drugs metabolized by CYP 450
Majority by CYP 34A/5 and CYP 2D6
See figure
Drug inducers and inhibitors
Different CYP subfamilies are affected by different inducers and inhibitors
Inducers increase CYP activity, less active drug available
Inhibitors decrease CYP activity, more drug available
See figure
Acetominophen, cocaine and testosterone inducers
Inducer: St. John’s wort
Inhibitor: Grapefruit juice
Need to be careful!
Where in metabolism do CYP 450 enzymes have the biggest role?
Phase II reactions
Examples of drugs altered in phase II reactions by CYP enzymes
Morphine -> morphine-6-gluro (pain reduction)
Minoxidil -> minoxidil sulfate (for hair growth)
Procainamide -> N-acetylprocainamide (for arrhythmia)
Transformation of morphine
See figure
Many CYPs involved
Examples of drugs that induce enzymes
Phenytoin: anticonvulsant medication. Overtime, causes increased expression of various cyp450 enzymes (cyp34A)
Rifampicin: antimicrobial, induces cyp450
Importance of induction
Mechanism that allows enzyme to change in response to xenobiotic
dynamic system that can respond to environment
Importance of induction from drug standpoint
PK- increased clearance; decreased half-life
PD- decreased response
Inducers and alterations of PK parameters
AUC: decreases (less bioavailable)
Cl (L/h): increases
T1/2: decreases
Cmax (max serum conc): decreases
Tmax (amount of time that drug is at max conc): increases
Other than drugs, what other factors can cause induction of enzymes?
environment/lifestyle factors (smoking)
herbal and nutritional supplements
Cimetidine as an enzyme inhibitor
Cimetidine-H2 receptor agonist
Used to treat peptic ulcer
Potent inhibitor of several cyp250 enzymes
Drug interactions: warfarin, benzodiazepines, phenytoin, morphine
PK and PD effects of cimetidine
PK: decreased Cl, increased T1/2
PD: increased response, increased duration
Enzyme inhibitor types of drug interactions
Drug A blocks metabolism of drug B
PD: increase response
PK: increase t1/2
Effects are immediate
Enzyme inducer types of drug interactions
Drug increases amt of enzymes for metabolism
Decreased response
Decrease plasma t1/2
Effects are delayed
Examples of inducers
Ethanol
Omeprazole
Phemobarbital
Rifampin
Smoking
Examples of inhibitors
Cimetidine
Erythromycin
Grapefruit juice
Ketoconazole
Quinidine
What are the three gene families under pressure for genetic variations
CYP gene family
UDP glucoronosyl transferase
N-acetyl transferase
CYP gene family genetic variations
Expression level
Enzyme Activity
Enzyme Induction
UDP glucoronosyl transferase genetic variability
Activity
N-acetyl transferase genetic variability
Expression level
CYP polymorphisms
see figure
CYP2D6 alleles
43 total (as of 2004)
24: no activity
6: decreased activity
* 2 variant can have 1,2,3,4,5 or 13 copies (increased activity)
CYP2D6 phenotype variation by race
caucasians highest frequency of PM phenotype
asians highest frequency of IM phenotype
africans highest frequency of the UM phenotype
Nortriptyline and CYP2D6
Active metabolite of nortryptiline is 10-hydroxynortriptlyline
Increasing number of copies of prodrug results in quicker elimination
Opposite for active drug
CYP2D6 and codeine - importance of genetic variability
Codeine -> morphine
0 copies: no metabolism, codeine is ineffective and maybe toxic
1-3 copies: adequate pharmacological response
13 copies: overdose?
Adverse responses to procainamide in slow and fast acetylators
Procainamide is used for tachycardia, but causes lupus
Slow acetylators develop adverse events more quickly
Reasons for variations in drug metabolism
Due to induction – other drugs, environment
Due to diet – natural inducers and inhibitors
Due to inhibition – disease processes and drugs
Due to genetics – defect in metabolic pathways
Due to development – special populations
Due to disease – impairment of organ function
How does age effect drug disposition?
Rate of drug disposition is most likely impaired in very young and very old
Importance of personalized medicine
Different patients have different expression of drug metabolizing enzymes, different diets and different backgrounds
Which organ if it became dysfunctional would be the most likely to affect drug metabolism?
Liver
Name two routes of drug administration that would be subject to 1st pass metabolism?
Oral
Rectal
What are the three outcomes of drug metabolism? Which is most common?
??
Routes of administration that avoid the 1st pass effect
suppository
intravenous
intramuscular
inhalational aerosol
transdermal
sublingual
