PHARM: Drug Metabolism Flashcards Preview

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Flashcards in PHARM: Drug Metabolism Deck (56):
1

What are the common characteristics of drug metabolizing enzymes?

Causes a chemical change in drug; forms more water-soluble metabolite; make metabolite more acidic ; terminates the drugs action

2

Where can cytochrome P450 be found in the body?

Highly concentrated on the ER of hepatocytes in the liver, but also in the SI, lungs, kidney, skin

3

What other enzyme is necessary for cyP450's action? What is the other's function w/ reference to cyP450?

NADPH Cytochrome P450 reductase; It transfers lectrons to P450

4

What is the general reaction performed by cytochrome P450?

Molecular oxygen (O2) is split; one atom of oxygen forms water and the other is added to the substrate as a hydroxyl group

5

How are cyP450s named?

CYP #(family) Letter(subfamily) 2nd # (individual)

6

What are the general classes of drug metabolizing reactions?

Non-synthetic Phase I and Synthetic Phase II

7

What class of drug metabolizing reaction is catalyzed by CYP450?

Phase I Non-Synthetic Oxidation Reactions

8

What is the major class of substrates metabolized by CYP1A?

Polycyclic hydrocarbons (naphthalene, benzopyrene)

9

What induces the expression of CYP1A?

Polycyclic hydrocarbons (found in cigarette smoke)

10

What are the major differences between CYP1A1 and A2?

A1 is only extrahepatic and is inducible by Aryl hydrocarbon receptor and A2 is constituitively and exclusively expressed in the liver but it is also inducible by exposure to broccoli, cauliflower, cigarette smoke and caffeine

11

What are the risks and potential consequences associated with CYP1A polymorphisms?

If people with hyper-active polymorphisms and are exposed to a lot of cigarette smoke they have a higher chance of developing lung cancer

12

What is metabolized by CYP1B1?

Polycyclic hydrocarbons, steroids, retinoic acid, arachidonic acid

13

What condition is caused by mutational deficiency in CYP1B1?

Primary Congenital Glaucoma

14

What are the primary forms of CYP2A in humans?

CYP2A6 and CYP2A13

15

What is metabolized by CYP2A6 and what are the consequences associated with polymorphisms in the enzyme? What can induce its expression?

Nicotine-- implications for nicotine dependence- those who can't metabolize nicotine as well suffer more from bad side effects when smoking; can be induced by phenobarbital and rifampicin

16

What is metabolized by CYP2A13 and where is it expressed?

Metabolizes nitrosamine, NNK, and is expressed in the resp. tract

17

What is the major form of CYP2B in humans?

2B6

18

What are the substrates of CYP2B6? What can its expression be induced by?

Metabolies MDMA, and are only metabolizers of polybrominated diphenyl ethers (flame retardants); inducible by phenobarbital, rifampicin, and phenytoin through constitutive active receptor

19

What is metabolized by CYP2C?

about 30% of commonly used drugs including omeprazole (Prilosec), Diazepam (Valium), and Clopidogrel (Plavix)

20

What is metabolized by CYP2D6?

Oral opiates (codeine, dextromethorphan, hydrocodone, oxycodone)

21

What is the drug interaction between Prozac and tamoxifen?

Tamoxifen is metabolized into its active form by CYP2D6 which is inhibited by some SSRIs, decreasing the effectiveness of tamoxifen

22

What is metabolized by CYP2E1?

EtOH and small hydrocarbons (benzene, toluene)

23

What CYP450 is inducible by ethanol?

CYP2E1

24

What is the mechanism of acetaminophen toxicity after taking acetaminophen with alcohol

Ethanol induces the upregulation of CYP2E1 expression causing more acetaminophen to be metabolized into harmful metabolite NAPQI

25

What CYP450 metabolizes over 50% of commonly used drugs?

CYP3A4

26

Which CYP450 is inducible by pregnane X receptor?

CYP3A4

27

What are common inhibitors of CYP3A4? Inducers?

Cimetidine and Grapefruit juice (bergamottin); Rifampicin and phenobarbital

28

What is the primary form of flavin monooxygenase in the adult? Primary form in the fetus?

FMO3; FMO1

29

What type of reaction is catalyzed by flavin monooxygenases?

N- and S- oxidation phase I reactions

30

What is trimethylaminuria and what is its basis?

Rare metabolic disorder due to polymorphism in FMO3, which metabolizes trimethylamines from breakdown of fish and meat, and so the individuals usually have a fishy odor

31

What reaction is catalyzed by alcohol dehydrogenase and what is the subsequent reaction and enzyme?

Ethanol is converted to acetaldehyde by alcohol dehydrogenase and then to acetic acid by aldehyde dehydrogenase

32

What are the three major types of reduction reactions?

Azoreduction, nitroreduction, ketoreduction

33

What are the types of hydrolysis reactions that occur in phase I drug metabolism

Esterase rxns, amidase rxns, and epoxide hydrolase rxns

34

What are the major 6 types of phase II conjugation rxns?

Glucuronidation, Sulfate conjugation, acetylation, glutathione conjugation, methylation, glycine conjugation

35

True or False: A simple hydrocarbon cannot be conjugated; it must undergo a phase I reaction first.

True

36

What are the main general functions of phase II conjugation reactions?

To make molecules more acidic and more water soluble

37

Which type of phase II conjugation reaction is quantitatively the most common reaction?

Glucuronidation

38

What enzymes catalyze glucuronidation reactions?

UDP-glucuronyltransferases

39

Drug molecules must have at least one of which functional groups to undergo glucuronidation?

Hydroxyl, carboxyl, amine, or sulfhydryl

40

What happens to a compound following glucurondiation?

It can be actively secreted into bile

41

What is enterohepatic cycling?

The process by which molecules (esp. amines, sulfhydryls) that are labile to acid or microbiota enzymes can be metabolized back into the parent drug and reabsorbed into circulation

42

What developmentally induced enzyme is responsible for bilirubin conjugation/metabolism

UGT1A1

43

Why are premature infants in danger of developing kernicterus?

Bilirubin is metabolism by UDP-glucuronosyltransferase 1A1 enzyme which is developmentally induced. Premature infants do not express adequate levels of this enzyme and so bilirubin can acculumate and cause kernicterus in the brain without intervention

44

What is kernicterus?

When bilirubin concentrations are high it can cross the BBB and cause CNS damage and ultimately death

45

What is Gray baby syndrome?

Occurs in infants given the antibiotic chloramphenicol, which requires a conjugation reaction catalyzed by UGT1A1 to clear. The build-up of the drug causes CNS damage, a gray appearance, and death

46

Crigler-Najjar syndrome: What is it?

A genetic disorder where an individual has a deficiency in UGT1A1-- typically fatal early in life

47

Why is it necessary for UGT2B4 to be expressed in fetuses?

Bile acids cannot cross the placenta and so the fetus must be able to metabolize their own, as well as some of mom's, bile acids

48

What enzymes catalyze sulfate conjugation reactions?

Sulfotransferases

49

What makes sulfate conjugation reactions saturable?

Sulfotransferases require PAPS, which is limited in the cell

50

What functional group undergoes acetylation reactions? What enzyme catalyzes these reactions?

Primary amines; N-acetyltransferase

51

What acetylation disorders are associated with slow acetylators? Rapid acetylators?

Isoniazid-induced neurotoxicity, Hydrolyzine-induced lupus, arylamine-induced bladder cancer; Isoniazid-induced hepatitis

52

What enzymes catalyze glutathione conjugation reactions? What product is formed?

Glutathione-S-transferases; mercapturic acids

53

Which conjugation reaction happens to reactive chemicals like eoxides, arylamines, and phenols?

Glutathione conjugation

54

What is associated with GSTM1 null mutations?

Cancer

55

What type of phase II conjugation reaction makes compounds more lipid-soluble?

Methylation reactions

56

True or False: Amino acid conjugation reactions can be saturated.

True