General Concepts Flashcards
- AUC is a measure of ______ based on the total area under the _____, as determined mathematically by _________.
- Depends on ____, _____, and _________.
- Related to CL how?
exposure, plasma concentration-time curve, trapezoid rule
Dose, F, CL
CL = DOSE / AUC
Vd- definition
- relationship to CL and t(1/2)
- relationship to plasma and tissue binding
- effect of binding on Vd
Proportionality constant relating half life to CL
Vd = CL x [t(1/2) / 0.693]
Vd = Vp + Vt (fu/fut)
Tissue vol influenced by degree of protein and tissue binding
Increase in protein binding without tissue binding changes will cause decrease in fu and a decrease in Vd
Primary route of elimination for most molecules
hepatic CL (CLliver usually = CLtotal body)
2 ways to reduce dose frequency
modify CL or Vdss
PD describes
relationship bw drug and concentration at receptor, and pharmacological/tox effects produced
Bioavailability is a measure of
rate and extent of absorption into systemic circulation
Absorption describes
rate and extent of drug entry into body following extravascular dosing
Which 2 PK parameters have an effect on ABSORPTION and DISTRIBUTION
F and V
First-pass metabolism definition, where can it occur
drug is absorbed from GI tract, passes via the portal vein into the liver where some drugs are metabolized, reducing amt that reaches systemic circ.
can occur in GUT and LIVER
For oral drug absorption, what is primary site? what is rate of absorption controlled by? which kind of drugs absorbed most rapidly?
for ORAL- primary site is small intestine, rate controlled by release of drug from dosage form
most rapid- unionized form
Following IV bolus, the drug is distributed by ________ , and the pattern of distribution depends on _________
distributed by blood flow, pattern of distribution depends on drug properties
Volume of distribution - definition? describes extent of distribution where?
equation that relates it to plasma conc?
V = APPARENT volume into which the drug is distributed to provide same concentration as plasma.
Describes extent of distribution outside sampling site.
V = AMT OF DRUG IN BODY / AMT OF DRUG IN PLASMA
Metabolism - definition
Excretion - definition
PK parameters?
metabolism- enzyme mediated change in drug
excretion- physical removal of molecule from body
PK parameters: CL (renal + metabolic = total)
Which drugs are eliminated more efficiently (in terms of lipophilicity)?
hydrophilic (polar) drugs
What is most important organ for excretion of drugs and metabolites? How else can drugs be excreted?
kidney (drugs also can be excreted in feces if unabsorbed oral drugs, or if the drug/metabolite is excreted in bile and not reabsorbed from intestinal tract)
Half-life - definition, relationship to CL and V
Time needed for half of drug to be eliminated from body
Depends on efficiency of metabolism and excretion (CL), and V
t(1/2) = Vd * 0.693/CL
What are the PK parameters for absorption? for metabolism and excretion?
absorption - F
metabolism / excretion = CL
allometry
half life is longer in larger animals
ECCS
framework to help identify major elimination pathway of a drug (small <400, big >400)
1- acid/zwit, high perm, 1a= small (metab), 2b= big (hepatic uptake)
2- base/neutral, high perm (metab)
3- acid/zwit, LOW perm, 3a= small (renal CL), 3b = big (renal CL or hepatic uptake)
4- base/ neutral, low perm (renal CL)
Compartment models vs. NCA
compartment- finite # of homogenous, well-mixed compartments, parameters are flow between compartments, Vc, etc.
NCA- no compartment structure, parameters determined by data inspection / approximating (AUC)
PBPK models take into account?
tissue volumes & flows
- each tissue divided into vascular, interstitial, cell spaces
- considers transfer / binding/ elimination mechanisms
What can limit F?
1st pass metabolism
What are the 2 phases of metabolism?
- primarily in liver
- Phase I- oxidation via cypP450, reduction, hydrolysis
- Phase 2- conjugation (glucuronidation, acetylation, sulfation), phase II converts parent drug to more polar inactive metabolites
Drugs metabolized via Phase I have ____. Drugs metabolized via Phase II are __________. Special populations?
- longer half lives
- renally excreted
- geriatric patients have decreased phase I, so they metab drugs via phase II.
- patients deficient in acetylation capacity (slow acetylators) may have prolonged or toxic responses to normal doses of drugs due to decreased metab.
low therapeutic index
drugs that move quickly from ranges that are therapeutic to toxic
What determines both half-life and first order elimination rate constant?
CL
What happens to half-life when Vd increases?
increases
What happens to half-life when CL increases?
decreases
The relationship between Vd and CL?
independent
Distribution is into _____, and is mediated by___ or _____.
What is a drug property that can limit distribution?
into extracellular and intracellular fluids, mediated by passive or transport-mediated.
high polarity can limit intracell access.
How is V related to plasma conc?
V = amount in body / plasma conc.
Excretion- most important organ?
What are the 3 component processes?
Important for which type of compounds?
Renal reabsorption may depend on ___.
- kidney
- filtration, active secretion and reabsorption
- polar compounds with MW <20kDa (remember ECCS)
- pH
Agonist
2 types?
drug that binds to receptor, mimics regulatory effect of endogenous signaling compounds
types- primary binds to same site, allosteric binds to diff region on receptor
Antagonist
-3 types
blocks/reduces action of agonist
-competitive, noncompetitive, functional (indirectly inhibit cell effects of agonist)
Receptor properties- contain both hydrophobic and hydrophilic segments of protein. Which is where?
hydrophobic: inside protein or in lipid bilayer
hydrophilic: on protein exterior surface
4 types of drug-receptor bonds in order of strength (weak to strong)
VHIC - Van der Waals, hydrogen, ionic, covalent
Van der Waals bonds
shifting e- density in areas of molecule results in transient + or - charges, which interact with opp. charge on another molecule
hydrogen bonds
hydrogen atoms bound to nitrogen or oxygen become more positively polarized, bind to more negatively polarized atoms like O, N, Sulfur
ionic bonds
atoms with excess of e- (overall negative charge) are attracted to atoms with deficiency of e- (overall positive charge)
covalent
2 bonding atoms share e-
What creates high affinity drug-receptor binding?
sum total of relatively weak interactions that create strong interaction (van der waals, hydrogen, ionic and covalent bonds)
affinity
how well drug binds to receptor, “tightness” of interaction
intrinsic activity
ability of drug to produce measurable effect after binding to a receptor
selectivity
how well drug binds the intended target vs. other proteins in the body
what are 4 aspects that influence drug-receptor binding?
affinity, intrinsic activity, selectivity, number of receptors available for binding
SAR helps determine?
structure activity relationship- can help determine which side chains are needed for which activities
Two ways to increase dissolution of oral compound
Decrease particle size (increases surface area so you get to final gut conc faster)
OR formulate compound as a salt which increases solubility so you get to higher conc.
5 methods of transport across enterocyte membrane
- passive diff. transcell
- trans-cytotic vessicles
- passive diff paracellular
- facilitated diff (carrier)
- active transport (transporter) - solute carrier family (SLC) or ATP-binding cassette (ABC) family
diffusion across membrane depends on? (2)
partition coefficient (how much molecule likes to go into membrane) and solubility
what form do drugs need to be in to cross membrane?
NEUTRAL (not acids or bases)
What is the diff between acids and bases absorption through lipid membrane?
Acids- are favored since in gastric juice, low pH, they’re pushed to neutral form and cross barrier into plasma. (still weak acids not very absorbed dt membrane thickness etc)
Bases- completely diff ratio, weak bases very disfavored in terms of absorption from stomach. BUT it drives dissolution into plasma, then can go into intestines with neutral pH and absorption favored`.
Cyps that make up majority of family?
cyp3A (80%)
cyp2C (18%)
factors impacting absorption?
surface area vascularity pH fluid vol. presence of other substances GI motility / emptying
what are the fundamental parameters controlling rate and extent of drug absorption
dissolution & GI permeability
-when dissolution rapid in relation to gastric emptying, rate/extent of absorption unlikely to depend on drug dissolution or GI transit time
When would a compound be considered highly soluble?
when the highest strength is soluble in 250mL or less, at pH 1-7.5
When would a compound be considered highly permeable?
when extent of absorption in humans is >90%
Will low permeability compounds be reaborbed?
no, will be excreted unchanged
how does food affect rate and extent of absorption
physical interaction, slows gastric emptying, prolongs GI transit time, raises pH, increases bile output/GI motility, inhibit transporters (bile, lipids)
What are 3 ways F can be predicted?
LogP (partition coeff b/w oxanol + H20)
Lipinski RoF
Caco-2 cells (A–>B
Lipinski Rule of 5
Poor oral absorption more likely when >5 H bond donors (OH+NH) >10 H bond acceptors (O+N) MW>500 logP>5 Exception- transporter substrates
What is the terminal phase of a conc-time profile reflective of?
the rate-limiting step! which is not necessarily the elimination rate as in flip-flop kinetics- could be absorption or diffusion etc.
What parameters can you get from NCA (IV)?
What is the assumption of NCA?
MRT, Cl, Vd
NCA assumes constant kinetic distribution parameters
MRT?
mean residence time- avg time a drug molecule spends in the system (normalized AUMC)
Define zero-order kinetics in terms of drug eliminations
What does this imply with regard to toxicity?
constant AMOUNT of drug eliminated over time REGARDLESS of plasma concentration.
Implies that absorption and elimination can become saturated, potentially leading to toxicity.
Define first-order kinetics in terms of drug elimination.
What is the drug elimination proportional to? What does this mean if you have higher plasma conc of drug?
a constant FRACTION of drug is eliminated over time via intrinsic half-life of drug.
Drug elimination is exponentially proportional to plasma conc (unlike zero-order kinetics).
Higher plasma conc will lead to exponentially higher drug elimination.
How might drug accumulate in first-order model of drug elimination?
If doses are delivered too frequently
Which two parameters can be used to determine steady state concentrations?
F and Cl
What might contribute to lack of specificity of pgp?
might be due to motion of nucleotide binding domains with respect to each other, which creates torque in TM domains that binds substrates, and allows Pgp to sample large potential substrate interaction sites
where does drug bind to pgp?
in the transmembrane domain of the transporter
BCS (biopharmaceutical classification system):
solubility / permeability
- high / high
- low / high
- high / low
- low/ low
What 3 factors are used for classifying in BCS?
- dissolution
- permeability
- solubility
compound is considered highly soluble if…
if highest dose strength dissolved in 250 ml or less of aqueous media
What is the relationship between A to B Perm(apparent) and fractional absorption?
Sigmoidal relationship (Papp as x axis, fraction absorbed as y). P(app) values above certain threshold are associated with high fractional absorption
For permeability assays, ref compound needs to have what % oral absorption? if a compound reaches this threshold, which class of BCS is it?
90% or higher oral absorption.
Class I or II
Describe permeability assay, ref compound, complications of assay?
Perm assay- CACO2 cells form monolayer, Apical side to lumen, basolateral side to blood (or insert inside well). Ref compound needs to be 90% or higher oral absorption in humans. Complications- low recovery if nonspecific binding, cytotox at high conc, etc.
What is the premise of the permeability assay’s use in BCS?
as long as compound is stable at gastric pH, it’s considered to be high permeable when permeability in the test system is higher than co-dosed ref compound whose fractional absorption in humans is at least 90%
What is the premise of Class I of the BCS?
Class I - high perm, high solubility. Assumed that for these compounds the fraction of the dose absorbed will be high and consistent from pt to pt –> get biowaiver –> replace some clinical studies with in vitro
How can pgp work against concentration gradient?
bc it relies on ATP
