drug metabolism

Question 1

processes that prevent continuous drug action

Answer 1

Elimination/ excretion
Metabolism- important for termination of drug action (for many drugs the metabolites are more easily excreted from the body, they are usually more polar and hydrophilic than the parent drug), metabolism of a drug can inactivate it, or it can activate a prodrug

Question 2

Drug drug interactions

Answer 2

often due to drug metabolism issues, the more drugs you administer the more likely the adver reactions are

Question 3

Phase 1 and phase 2 enzymes

Answer 3

Phase 1: oxidation, reduction, dealkylation, or hydrolysis; they typically introduce or reveal a functional group

Phase 2: conjugation of a drug/metabolite to an endogenous substrate molecule

Question 4

localization of drug metabolizing enzymes

Answer 4

Organ distribution: portals of entry and exit, liver (highest overall), GI tract, all tissues have some, varies significantly for specific enzymes

Subcellular distribution: Phase 1 enzymes typically in SER, phase 2 enzymes (most are cytosolic)

Question 5

1st pass effect

Answer 5

for orally administered drugs, following absorption from GI tract, the portal venous system transports them to the liver, significant drug metabolism can occur before reaching the general circulation (hepatic/intestinal)

Significance: can greatly lower the oral bioavailability of a drug, drugs with a large 1st pass effect need higher oral doses

Question 6

phase 1 reactions enzymes

Answer 6

CYP450s, flavin containing monooxygneases

Question 7

What do you need for CYP 450 reactions

Answer 7

heme, O2, NADPH reductase, single isoform of P450 reductase in all cell types

Many different isoforms of cytochrome p450, with a molecular ratio of 10-20 p450s per p450 reductase

Question 8

human cyp450s

Answer 8

18 families but 3 main ones involved in drug metabolism (CYP1, CYP2, CYP3) with 15 human genes, with individual differences in isoform expression and catalytic activity…can result in large differences in drug metabolism

CYP3A: 50%
CYP2D6: 25%
CYP2C9: 15 %

BUT relative CYP isoform content doesnt = significance in drug metabolism

lots of CYPs are expressed in high levels even tho 3A, 2D6, and 2C9 are the major metabolizers of most drugs

Question 9

Flavin-containing monooxygenases

Answer 9

MOO reactions: substrates have soft nucleophiles, exclude non substrates

with a broad substrate profile than P450s, even broader substrate profile than p450s

products are usually more polar and less toxic

Use NADPH and FADH

FMO3 mainly in liver

Question 10

Phase 2 reactions

Answer 10

gsh conjugation sulfation acetyl ations

Broad substrate specificities, some are inducible, Vmax affected by conventional kinetics and finite supply of conjugant molecules

Question 11

possible order and cooperativity of phase 1 and 2 enzymes

Answer 11

drug-> phase 1 -> excretion
drug -> phase 1 -> phase 2 -> excretion
drug -> phase 2 -> excretion
drug-> phase 2 -> phase 1 -> excretion

Question 12

phase 2 reactions, conjugation capacity, and abundance of raw materials for conjugation

Answer 12

Glucuronidation: high capacity, high abundance
Sulfation: low capacity, low abundance
Glutathione conjugation: low capacity, low abundance
Acetylation: variable capacity, variable abundance

Question 13

enzyme induction

Answer 13

exposure to some drugs and environmental chemical markedly up regulates drug metabolizing enzyme amount and or activity (usually due up regulation of transcription

more enzyme= faster metabolism

ethanol induces CYP 2E1
CYP2D6 is not very inducible

a single inducer can affect many drugs handled by that enzyme

induction can increase or decrease drug effects depending on whether metabolite is active or inactive

Decreased effectiveness, or increased effects/toxicity

Enzyme induction can take 1-2 days, and takes days to weeks to return to non induced levels once inducer is removed
not all inducers work as fast

Question 14

CYP 2D6

Answer 14

Not very abundant (1.5% of total CYP450 content)
handles 25% of all drugs
not very inducible
makes it very susceptible to competitive inhibition

Question 15

does an inducer have to be a substrate

Answer 15

not all substrates are inducers, some inducers are substrates and some are not

Question 16

inhibitors of drug metabolizing enzymes

Answer 16

usually activity decreases (not gene expression)

Competitive or non competitive

Question 17

3 types of p450 inhibitors

Answer 17

competitive substrates: major cause of CYP-related drug interaction, can also effect phase 2 enzymes

non-competitive: bind non substrates site to disrupt conformation/activity, bind to CYP-heme group and blocks catalytic activity, there are some reversible inhibitors

inhibition is immediate and is variable in effect, several inhibitors of CYP2D6 can reduce its activity to zero–> zero order kinetics

Question 18

grapefruit juice

Answer 18

CYP inhibition, (via furanocoumarin)

increases absorption of drugs that are inactivated by CYP 3A inhibits intestinal CYP3A

Question 19

FMO induction and inhibition

Answer 19

FMOs are not significantly induced or inhibited by clinically used drugs

drugs that are handled by FMO have less potential for metabolic drug-drug interaction

Question 20

factors that influence drug metabolism activity

Answer 20

AGE, Genetics, Disease state, Gender (women require half the dose of zolpidem)

Even tho CYP3A expression is overall similar between men and women, the clearance in women is slower

6-7% of drugs have >40% pharmocokinetics differences between men and women

neonates have a longer drug t1/2