Drug Metabolism

Question 1

Biotransformation

Answer 1

AKA drug metabolism, converting lipophilic chemicals to hydrophilic chemicals usually by enzymes for excretion from the body by urine or bile

Question 2

Acetaminophen Metabolism example

Answer 2

glucuronidation and sulfation metabolism result in non-toxic metabolites, but oxidation via CYP2E1 or CYP3A4 leads to a toxic quinone amine

Question 3

MDTP metabolism example

Answer 3

people tried to synthesize Demerol made MDTP on accident. MDTP crosses BBB, metabolized by MAO-B to MPP+ which inhibits dopamine uptake killing dopaminergic neurons leading to parkinsonism

Question 4

Terfenadine metabolism example

Answer 4

Prodrug of fexfenadine. If taken concomitantly with ketoconazole, erythromycin or grapefruit juice (CYP3A4 inhibitors) then torsade de pointes may occur

Question 5

Phase 1 Metabolism

Answer 5

Oxidation, reduction and hydrolysis - add or reveal functional group

Question 6

Phase 2 Metabolism

Answer 6

Conjugation of a function group on a xenobiotic with an endogenous molucules

Question 7

Fast Pass Effects

Answer 7

Metabolism in intestine and/or liver may change bioavailability of drug before they can reach target tissue

Question 8

Xenobiotic-sensing receptors

Answer 8

Increases xenobiotic metabolizing enzymes levels in the presence of the drug, aryl hydrocarbon and pregnane X receptor

Question 9

Biotransformation of Drugs

Answer 9

Can increase, decrease or have no effect on pharmacologic activity. EX. Codeine has no activity until CYP2D6 changes it to morphine

Question 10

Oxidation

Answer 10

Gain of oxygen and/or loss of hydrogen atoms

Question 11

CYP450

Answer 11

Family of enzymes note: Inducible, developmentally and tissue specific, catalytically versatile. Found in haptocyte ER or mitochondria, contain Heme

Question 12

Clinically important CYP450s

Answer 12

CYP3A4 (most abundant in liver) and 5, CYP2D6, CYP2D8 and 9

Question 13

CYP450 basic reaction

Answer 13

1 oxygen atom (why they’re called monooxygenases) added to a substrate and the other reduced to water: RH + O2 + NADPH + H+ –> ROH + H2O + NADP+

Question 14

Reduction

Answer 14

Gain of H atoms, loss of O

Question 15

Azo and Nitro reduction

Answer 15

Catalyzed by intestinal microflora

Question 16

Carbonyl reduction

Answer 16

Aldehydes and ketones, aldo-ketoreductasesa dn short-chain dehydrogenases/reductases

Question 17

Hydroloysis

Answer 17

Cleavage of bond by the addition of water. Mostly catalyzed by carboxylesterases, also by epoxide hydrolases (important post CYP450 epoxide detoxify-er) , cholinesterases, petidases. Example: metabolism of procaine to Novocain or Benzo[a]pyrene to a tumorigenic metabolite

Question 18

Conjugation reactions

Answer 18

Involve high energy intermediates and specific transfer enzymes. Usual produce more polar species than parent substrates

Question 19

Glucuronidation

Answer 19

Transfer of glucuronic acid from UDP-glucuronic acid to nucleophilic heteroatom on a substrate by UDP-glucuronosyltransferase (UGT) in liver

Question 20

Sulfation

Answer 20

Transfer of sulfonate group from 3-phophoadenosine-5’-phophosulfate (PAPS) to an available group on substrate catalyzed by cytosolic sulfotransferases (SULT)

Question 21

Glutathione conjugation

Answer 21

Catalyzed by glutathione transferases (GST) in multiple cellular compartments

Question 22

Acetylation

Answer 22

transfer of acetyl group from co-factor acetyl co-enzyme A to amino group on substrate, catalyzed by N-acetyltransferases.

Question 23

Methylation

Answer 23

Methyl group from S-adenosylmethionine to electron rich (O, N, S) heteroatom. Usually decreases water solubility

Question 24

Amino acid conjugation

Answer 24

xeno carboxylic acid to amino group of AA or xeno aromatic hydroxylamine with AA carboxylic acid