Drug Metabolism Flashcards Preview

Pharmacology Basic Principles > Drug Metabolism > Flashcards

Flashcards in Drug Metabolism Deck (24):
1

Biotransformation

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

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Acetaminophen Metabolism example

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

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MDTP metabolism example

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

4

Terfenadine metabolism example

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

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Phase 1 Metabolism

Oxidation, reduction and hydrolysis - add or reveal functional group

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Phase 2 Metabolism

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

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Fast Pass Effects

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

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Xenobiotic-sensing receptors

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

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Biotransformation of Drugs

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

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Oxidation

Gain of oxygen and/or loss of hydrogen atoms

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CYP450

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

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Clinically important CYP450s

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

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CYP450 basic reaction

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+

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Reduction

Gain of H atoms, loss of O

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Azo and Nitro reduction

Catalyzed by intestinal microflora

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Carbonyl reduction

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

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Hydroloysis

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

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Conjugation reactions

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

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Glucuronidation

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

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Sulfation

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

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Glutathione conjugation

Catalyzed by glutathione transferases (GST) in multiple cellular compartments

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Acetylation

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

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Methylation

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

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Amino acid conjugation

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