Drug Disposition: Metabolism

Question 1

(1) What general process occurs most commonly during drug metabolism that renders them therapeutically inactive?

Answer 1

metabolism changes the chemical structure resulting in altered pharmacology and solubility, usually increasing the polarity of drug which makes it more soluble and easy to excrete (more rarely metabolism produces active or toxic products)

Question 2

(1) Which is the major organ of biotransformation?

Answer 2

liver, but also kidney, lung and intestine

Question 3

(1) What is the first-pass effect.

Answer 3

term describing the metabolism of drug that is ingested and absorbed through the gut, before it reaches the systemic circulation

Question 4

(2) What occurs in a phase 1 reaction?

Answer 4

(aka functionalization) oxidative, hydrolytic and reductive reactions occur that alter, cleave or create new chemical functional groups

Question 5

(2) Contrast the two different type of phase I reactions: oxidative/reductive and hydrolytic

Answer 5

oxidation/reduction reactions alter or create new chemical functional groups
hydrolytic reactions cleave groups to reveal other functional groups

Question 6

(3) Name the five major isoforms of cytochrome P450 enzymes.

Answer 6

CYP1A2, CYP2C9, CYPC19, CYP2D6 and CYP3A4 (these participate in the metabolism of at least ½ of all drugs)

Question 7

(4) What cofactors are required for the action of CYPs?

Answer 7

both NADPH and O2

Question 8

(4) Which CYP is most susceptible to genetic variation?

Answer 8

CYP2D6

Question 9

(4) Describe the chemical steps used by P450 enzymes to oxidize drugs

Answer 9

1. ferric form of P450 binds drug
2. retransfers e- from NADPH to P450
3. now ferrous form of Fe can bind molecular O2
4. 2 H+ are added to complex and water is given off (loss of e-)
5. ferric state lets go of substrate bound to OH group (oxidized)

Question 10

(5) Name 7 major chemical transformations catalyzed by CYPS. (STUDY THIS)

Answer 10

1. aliphatic and aromatic hydroxylation (adding OH group)
2. alkene and aromatic epoxidation (formation of epoxide)
3. N-, O- and S- dealkylation (removal of akyl group)
4. N-oxidation and N-hydroxylation (add O to N group)
5. oxidative deamination and desulfuration (O replaces N group or S)
6. S-oxidation (carboxyl group replaces S)
7. oxidative dehalogenation (carboxyl group replaces halogen)

Question 11

(6) Name 6 other enzymes involved in Phase 1 reactions.

Answer 11

1. flavin adenine dinucleotide (FAD) monooxygenase
2. monoamine oxidase
3. diamine oxidase
4. alcohol dehydrogenase
5. aldehyde dehydrogenase
6. xanthine oxidase

Question 12

(6) Give examples of reactions carried out by non-p450 enzymes.

Answer 12

?

Question 13

(7) What is a phase 2 reaction?

Answer 13

generally a phase 2 reaction couples a polar group onto a functionalized substrate (often follows phase I reaction, although this is not necessary)

Question 14

(7) Name 5 distinct phase 2 reactions (hint- increase solubility)

Answer 14

1. glucuronidation
2. sulfation
3. mercapturic acid formation
4. N-, O-, S-methylation
5. acetylation

Question 15

(8) What is the mechanism and enzyme for glucuronidation?

Answer 15

uridine diphosphate-glucuronyl transfrase (UGT), adds glucuronic acid to hydroxyls, carboxylic acids, thiols or amines, addition of glucuronic acid creates a very polar molecule

Question 16

(8) What is the mechanism and enzyme for sulfation?

Answer 16

sulfotransferases attach a sulfate group to a hydroxyl group (ie. 3’-phosphoadenosine-5’-phosphosulfate PAPS is a donor of sulfate) addition of sulfate greatly increases molecular weight

Question 17

(8) What is the mechanism and enzyme for mercapturic acid formation? (multi step)

Answer 17

glutathione S transferase (GST) ads glutathione (Glys, Cys, Glu) to acceptor molecule followed by hydrolysis of glutamate and glycine (cysteinyl glycinase), then acetylation of cysteine (N-acetyl transferase)

Question 18

(8) What is the mechanism and enzyme for N-, O-, S-methylation?

Answer 18

methyltransferases add a methyl group from S-adenosyl methionine to acceptor molecules

Question 19

(8) What is the mechanism and enzyme for acetyl transfer?

Answer 19

2 isoforms of aryl amine N-acetyltransferase (COMT) catalyze the transfer of acetyl group from acetyl CoA to various amine and hydrazine acceptor molecules

Question 20

(9) How do xenobiotics can produce increases in drug metabolism.

Answer 20

different triggers (xenobiotics) cause the increased gene transcription of enzymes that metabolize drugs (ie. CYP, GST, and UGT enzymes)

Question 21

(9) Name 3 substances that can induce cytochrome P450.

Answer 21

anticonvulsants, St. John’s wort, HIV drugs, Rifampin, glucocorticoids, polycyclic aromatic hydrocarbons (grilling or smoking)

Question 22

(10) Explain how xenobiotics can produce decreases in drug metabolism. (4)

Answer 22

1. cofactor depletion
2. reversible competitive inhibition (compete for binding site)
3. covalent inhibition where reactive intermediates modify and inactivate enzymes
4. pseudo irreversible inhibition (high affinity intermediates are slow to dissociate from active site)

Question 23

(10) Name 3 substances that block the metabolism of other drugs.

Answer 23

antibiotics (decreases enteric circulation)
azole-antifungals (inhibit CYPs)
grapefruit juice (inhibits CYPs)

Question 24

(11) Give examples of how age, environmental factors and disease can affect drug metabolism

Answer 24

age: hepatic metabolism is mature at 1 year and elderly patients have lower hepatic metabolic activity

nutritional status: protein and iron deficiency leads to decreased CYP metabolism

pathological state

Question 25

(11) Name 3 drugs whose metabolism is affected by genetic variation.

Answer 25

warfarin, omeprazole, codeine, most SSRIs, many antipsychotics and beta-blockers

also
COMT deficiency- isoproterenol
Thiopurine-S-methyltransferase def- azathioprine
butyrylcholinesterase activity: succinylcholine sensitivity and resistance