Metabolism/Excretion

Question 1

Where does metabolism occur in body

Answer 1

Liver (primary), Intestine, Lung (30%), kidney (8%), placenta (5%)

Question 2

Point of metabolism

Answer 2

to convert lipid soluble compounds to more water soluble (polar) compounds so they are more readily excreted

Question 3

Most common metabolic outcome

Answer 3

inactivating/detoxifying process(95%)

Question 4

Less common outcomes of metabolism

Answer 4

active drug to more active compound (codeine to morphine), inactive prodrug to active drug, metabolism to toxic metabolite

Question 5

Reaction types in Phase I metabolism

Answer 5

Oxidation by CYP450, hydrolysis, reduction

Question 6

Enzymes in Phase I reactions

Answer 6

CYP45- (oxidation)
esterases/ amidases (hydrolysis)
reductases (reduction)

Question 7

Phase II reactions

Answer 7

conjugations

Question 8

Phase II enzymes

Answer 8

transferases

Question 9

importance of genetic polymorphisms in Metabolism

Answer 9

significant for both Phase I and II

Question 10

Inducers and inhibitors

Answer 10

Phase I - significant

Phase II – possible-less

Question 11

Development patterns/age changes

Answer 11

variable/Decrease in 1/3 for phase I; variable/minimal for Phase II

Question 12

Saturability of Phase I and II

Answer 12

Phase I – minimal
Phase II – substantial; Limited supply of reactants renders Phase II reactions more easily saturable (become zero order elimination kinetics) than phase I reaction

Question 13

Purpose of Phase I

Answer 13

inserts/unmasks a functional group to make drug more water soluble

Question 14

Required molecules in Phase I reactions

Answer 14

O2 and NADPH

Question 15

Purpose of Phase II

Answer 15

Endogenous substrate combines with pre-existing or metabolically inserted functional group (via Phase I) on drug. Now highly polar and readily excreted

Question 16

Types of Phase II reactions

Answer 16

glucuronidation, acetylation, glutathione/glycine/sulfate conjugation

Question 17

Functional groups added in Phase I, examples

Answer 17

-OH, SH, NH2

Question 18

Inducers

Answer 18

Phenobarbital, Phenytoin, Carbamazepine, Rifampin, Ethanol, St John’s wort, Tobacco/marijuana smoke

Question 19

Inhibitors

Answer 19

cimetidine, erythromycin/clarithromycin, antifungal agents, omeprazole, grapefruit juice, fluoxetine (and other SSRIs)

Question 20

Rate of renal blood flow

Answer 20

600 ml/min

Question 21

rate of glomerular filatration

Answer 21

120 ml/min

Question 22

How to trap weak base in urine

Answer 22

acidify urine with NH4CL/ascorbic acid

Question 23

How to trap weak acid in urine

Answer 23

alkalinize urine with NaHCO3

Question 24

Three main processes occurring at the kidney

Answer 24

Drug filtered at glomerulus, active secretion at proximal convoluted tubules, passive reabsorption

Question 25

implications of enterohepatic recirculation of drugs

Answer 25

keeps free form of drug out of plasma -- increased duration of action/reduce elimination/prolong half-life

Question 26

enterohepatic recycling

Answer 26

drugs/metabolites with large molecular weights (>300) may be excreted via bile, stored in gallbladder, delivered to intestines via bile duct, and then reabsorbed into circulation where it can return to liver via superior mesenteric and portal veins.