Absorption and Distribution

Question 1

Determinants of bioavailability of a drug (4 things)

Answer 1

1. solubility and ability of drug to resist decomposition in GI lumen 2. ability of drug to permeate and resist metabolism within GI epithelium 3. resist metabolism in the portal circulation 4. resist metabolism within the liver

Question 2

Drug delivery methods that do not have first pass effects

Answer 2

IV, buccal/sublingual, rectal (partially)

Question 3

Factors affecting distribution from plasma (5 things)

Answer 3

1. capacity to cross cell membrane 2. endothelial cell layer continuity (fenestration, leakyness) 3. blood flow (perfusion) 4. binding of drugs to plasma proteins 5. partitioning into fat or binding to tissue compartments

Question 4

Why does binding of drugs to plasma protein matter? (4 things)

Answer 4

1. free drug is active 2. protein bound cannot necessarily be filtered, nor is it readily transported into hepatocytes (but can be by renal tubular epithelium) 3. degree to which a drug binds to protein can vary with disease and other physiological states 4. other drugs/endogenous substances can compete for binding with protein-bound drugs

Question 5

Effects of drug displacement from plasma protein

Answer 5

usually not a big deal since albumin has a high capacity for binding and drug elimination is 1st order; but if drug has a small therapeutic index or if displacement prevents excretion then there can be problems

Question 6

Which CYP contribute to the vast majority of drug clearance? (3)

Answer 6

CYP2D6, 3A4, 2C9

Question 7

Components of renal excretion of drugs (2 things)

Answer 7

1. Glomerular filtration: MW < 20k can pass into filtrate, 20% of RPF delivered to glomerulus, anything bound to albumin will not be filtered
2. Carrier mediated transport (PCT) is more important mode of drug excretion: weak acids, organic bases, extremely effective and not limited by plasma protein binding

Question 8

CYP inducers:

Answer 8

barbiturates, carbamazepine, glucocorticoids, macrolide abx, glitazones, phenytoin, rifampin

Question 9

CYP inhibitors

Answer 9

diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, ritonavir