Drug Metabolism

Question 1

Structural modification of the drug via oxidation, reduction, or hydrolysis:

Answer 1

Phase 1 Reactions

Question 2

Consequences of phase 1 modifications:

Answer 2

1. inactivation of the parent drug
2. conversation of active drug to an active drug metabolite
3. conversion to a toxic metabolite
4. generation of a “reactive” metabolite
5. conversion of an inactive drug to an active drug metabolite

Question 3

Also called conjugation reactions because produce of phase 1 reaction is conjugated to a large, endogenous molecule:

Answer 3

Phase 2 Reactions

Question 4

Conjugation almost always results in conversion of drug to inactive metabolite that are highly:

Answer 4

ionized, polar, hydrophilic

Question 5

Action of drug efflux transporters regulates bioavailability, distribution, and excretion of drugs; act in concert with. phase I and II enzymes to reduce systemic exposure to xenobiotics:

Answer 5

Phase 3 Reactions

Question 6

Contribute to endothelial barrier function:

Answer 6

Phase 3 Reactions

Question 7

Most important site of enzymes that metabolize and transport drugs:

Answer 7

Liver - greatest concentration of metabolizing enzymes

Question 8

T/F. Hepatic metabolism is not high enough to remove most of the drug from the portal blood passing through the liver.

Answer 8

False; hepatic metabolism IS high enough.

Question 9

First-pass or presystemic metabolism is referring to:

Answer 9

metabolism in the liver; oral drugs transported via portal vein

Question 10

Subcellular locations of drug metabolizing enzymes/transporters for Phase 1 enzymes, Phase 2 enzymes, and Phase 3 transporters:

Answer 10

Phase 1 enzymes: smooth endoplasmic reticulum of the liver;
Phase 2 enzymes: cytosol, enzymes are soluble (except UGTs in SER);
Phase 3 transporters: apical (luminal side) and basolateral (blood side) membranes of GI and renal tubular epithelial cells, plasma and canalicular membranes of hepatocytes

Question 11

Cytochrome P450 Complex (CYP) is what kind of enzyme?

Answer 11

Phase 1 enzyme

Question 12

The net result of CYP-catalyzed oxidation (hydroxylation) reaction is:

Answer 12

Drug + O2 +NADPH + H+ –> Drug-OH + H2O + NADP+

Question 13

Nomenclature: How to name CYP gene superfamily:

Answer 13

CYP + family number + subfamily letter + individual gene number, ex: CYP1A2, CYP2D6

Question 14

Three CYP isozymes that account for the metabolism of most drugs:

Answer 14

CYP 3A4/5, 2C8/9, 2D6

Question 15

Amine oxidases, dehydrogenase, flavin-containing monooxygenase (FMO), reductases are what kind of enzymes:

Answer 15

Phase 1 enzymes

Question 16

Monoamine oxidase (MAO); oxidize endogenous catecholamine neurotransmitters and synthetic analogs:

Answer 16

amine oxidases

Question 17

Alcohol (ADH) and aldehyde (ALDH) dehydrogenases, oxidize alcohols to aldehydes and aldehydes to acids:

Answer 17

Dehydrogenases

Question 18

Oxidizes substrates with N-, S-, P- moieties, not C, similar to CYPs but are only minor contributors to drug metabolism, can metabolize nicotine, some H2 receptor antagonists, and antipsychotics

Answer 18

Flavin-containing monooxygenase (FMO)

Question 19

Carry out reduction of ago-, nitro-, and carbonyl groups on drug molecules, located in the liver and in anaerobic bacteria of the GI tract

Answer 19

reductases

Question 20

Hydrolysis inactivates some parent ester drugs, but activates other ester prodrugs (bioactivation) (esterification improves oral bioavailability) with these enzymes:

Answer 20

Hydrolytic enzymes

Question 21

Carboxylesterases, amidases, epoxide hydrolase (EH) are examples of what kind of enzymes?

Answer 21

Hydrolytic

Question 22

Acetylcholinesterase (neurons) and butyrylcholinesterase (plasma) hydrolyze ester-containing drugs, acetylcholine and its synthetic analogs; bioactivation of lovastatin (pro-drug) inhibits formation of mevalonate (precursor for cholesterol), what enzyme is this?

Answer 22

carboxylesterases

Question 23

This enzyme hydrolyzes amide linkages in drugs:

Answer 23

amidases

Question 24

This enzyme hydrolyses epoxide metabolites produced by CYP-mediated metabolism of aromatic rings (epoxides are reactive metabolites):

Answer 24

epoxide hydrolase (EH)

Question 25

Conjugation or synthetic reactions refers to these types of enzymes:

Answer 25

Phase 2 enzymes

Question 26

Where are phase 2 enzymes mostly found and what is the exception?

Answer 26

cytosol (except UGTs in SER)

Question 27

These enzymes use reactive of functional groups on drugs or drug metabolites to covalently combine an endogenous molecule:

Answer 27

Phase 2 enzymes

Question 28

Acceptor site functional groups of Phase 2 enzymes:

Answer 28

hydroxyl, epoxide, nitrite, amine, sulfide

Question 29

Endogenous donor molecules of phase 2 enzymes:

Answer 29

glucoronic acid, sulfate, glutathione, amino acids, or acetate

Question 30

Phase 2 enzymes have what effects on drugs?

Answer 30

1. inactivates 2. usually makes drug more polar 3. greater molecular weight 4. more easily excreted in bile and urine

Question 31

UDP-glucuronyltransferase (UGT) is what type of enzyme?

Answer 31

Phase 2 enzyme

Question 32

UGT is only phase 2 enzyme found where?

Answer 32

SER (not cytosolic), it is in Cole proximity with CYPs

Question 33

T/F. UGT attaches glucuronic acid to acceptor sites (OH, NH2, COOH, sulfonamide) on drug substrates. And the enzyme produces what metabolite?

Answer 33

TRUE, produce "glucuronide conjugate" metabolite

Question 34

UGT1 and UGT2 are involved in conjugation of?

Answer 34

Drugs and bilirubin

Question 35

Attaches sulfo- groups to acceptors sites (-OH groups) on drug substrates

Answer 35

sulfotransferase (SULT); "sultan conjugate" metabolite which is very polar

Question 36

Attaches glutathione (GSH) to acceptor sites on substrates (which are often reactive metabolites of certain drugs)

Answer 36

Glutathione-S-transferase (GST); produce a "GSH conjugate" metabolite

Question 37

Attaches acetate to aromatic amine and hydrazine drug substrates:

Answer 37

N-acetyltransferase (NAT); produces an "acetylated" metabolite; two human acetylkator genes: NAT1, NAT2

Question 38

Methylates various substrates:

Answer 38

Methyltransferase (MT)

Question 39

These enzymes metabolize over 80% of all drugs:

Answer 39

NATs, GSTs, UGTs, and SULTs

Question 40

Types of Phase III Enzymes:

Answer 40

ATP Binding Cassette (ABC) Transporters, SoLute Carrier (SLC) Transporters

Question 41

Rate of metabolism can control ______ and _____.

Answer 41

Drug Efficacy and Toxicity

Question 42

What is the major source of adverse drug interactions?

Answer 42

Drug Metabolism

Question 43

8 factors influencing drug metabolism:

Answer 43

enzyme induction, enzyme inhibition, pharmacogenetics, age, nutrition and diet, disease, hormonal effects, intestinal microflora

Question 44

The increase in concentration of metabolizing enzymes or transporters following exposure to xenobiotics; up-regulation:

Answer 44

Induction

Question 45

Enzyme inducing xenobiotic examples:

Answer 45

Tobacco smoke and charbroiled foods - CYP1a (carcinogens), Ethanol - CYP2E1 (acetaminophen), St. John's wort (herbal) - CYP3A4, MDR1

Question 46

Xenobiotic sensing receptors:

Answer 46

Inducers (enzyme induction)

Question 47

Examples of xenobiotic sensingg receptors:

Answer 47

MDR1, OATP2, UGT1A2, GSTA1

Question 48

Consequences of enzyme induction:

Answer 48

1. diminish plasma drug levels to below therapeutic levels 2. may increase toxic metabolites 3. Long term chronic exposure may induce enzyme levels that never return to baseline after cessation (smoking induced expression of CYP1A)

Question 49

Diminishes rate of enzyme activity:

Answer 49

Enzyme inhibition

Question 50

Terms to describe inhibition ceasing when inhibitor eliminated vs. when inhibitors are irreversible:

Answer 50

competitive vs. non-competitive

Question 51

Consequences of inhibition:

Answer 51

drug-drug interactions when taking multiple drugs, one drug inhibits the metabolism of another

Question 52

Examples of inhibiting enzymes:

Answer 52

grapefruit juice (CYP3A4, 1A2, 2B6 in intestine), Antifungals and histamine antagonists in liver, HIV-1 protease inhibitors inhibit CYP 3A4

Question 53

Why is it important to have accurate history of all reactions and drug combinations of your patient?

Answer 53

to avoid drug-drug interactions

Question 54

Addresses the influence of genetic variations on drug responses:

Answer 54

Pharmacogenetics

Question 55

Polymorphisms- Populations with tri-modal activities of:

Answer 55

poor (gene deleted), rapid (wild type), and ultra-rapid (gene duplicated)

Question 56

Examples of Phase 1 Enzyme Polymorphisms:

Answer 56

CYP2D6 = antiarrhythmics, beta-blockers, CYP2C9 = warfarin, phenytoin, CYP2C19 = warfarin, antidepressants, CYP3A4 = few polymorphisms affect enzyme activity

Question 57

Effects of inactive or multiple CYP2D6 genes:

Answer 57

1 functional group = SLOW, exhibit toxic drug effects, 13 functional groups = RAPID, exhibit no beneficial effects of drug

Question 58

Examples of Phase II Enzyme Polymorphisms:

Answer 58

NAT2 (n-acetyl transferase-2) and UGT1A1 (glucuronidation of bilirubin)

Question 59

Difference between NAT2*4 vs. NAT2*5:

Answer 59

NAT2*4 = rapid acetylator (US asians) vs. NAT2*5 = slow acetylators (US whites and blacks)

Question 60

Gilbert's Syndrome is related to what polymorphism:

Answer 60

UGT1A1*28, TATA Box

Question 61

A 70-80% reduction in UGT activity results in:

Answer 61

HYPERbilirubinemia leading to coronary artery disease

Question 62

The study to devise drug regimens to maximize efficacy and minimize adverse effects

Answer 62

Pharmacogenetics

Question 63

How does age influence drug metabolism?

Answer 63

The older you are, the more drugs you probably take. Therefore, start with a low dose and give very slowly to help with adverse drug effects. Use Phase II (UGT) more in elderly or those with liver disease.

Question 64

Intestinal microflora can diminish Beta-glucuronidases. T/F.

Answer 64

True, bacteria plays role.