Drug Metabolism Flashcards
Biotransformation
AKA drug metabolism, converting lipophilic chemicals to hydrophilic chemicals usually by enzymes for excretion from the body by urine or bile
Acetaminophen Metabolism example
glucuronidation and sulfation metabolism result in non-toxic metabolites, but oxidation via CYP2E1 or CYP3A4 leads to a toxic quinone amine
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
Terfenadine metabolism example
Prodrug of fexfenadine. If taken concomitantly with ketoconazole, erythromycin or grapefruit juice (CYP3A4 inhibitors) then torsade de pointes may occur
Phase 1 Metabolism
Oxidation, reduction and hydrolysis - add or reveal functional group
Phase 2 Metabolism
Conjugation of a function group on a xenobiotic with an endogenous molucules
Fast Pass Effects
Metabolism in intestine and/or liver may change bioavailability of drug before they can reach target tissue
Xenobiotic-sensing receptors
Increases xenobiotic metabolizing enzymes levels in the presence of the drug, aryl hydrocarbon and pregnane X receptor
Biotransformation of Drugs
Can increase, decrease or have no effect on pharmacologic activity. EX. Codeine has no activity until CYP2D6 changes it to morphine
Oxidation
Gain of oxygen and/or loss of hydrogen atoms
CYP450
Family of enzymes note: Inducible, developmentally and tissue specific, catalytically versatile. Found in haptocyte ER or mitochondria, contain Heme
Clinically important CYP450s
CYP3A4 (most abundant in liver) and 5, CYP2D6, CYP2D8 and 9
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+
Reduction
Gain of H atoms, loss of O
Azo and Nitro reduction
Catalyzed by intestinal microflora
Carbonyl reduction
Aldehydes and ketones, aldo-ketoreductasesa dn short-chain dehydrogenases/reductases
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
Conjugation reactions
Involve high energy intermediates and specific transfer enzymes. Usual produce more polar species than parent substrates
Glucuronidation
Transfer of glucuronic acid from UDP-glucuronic acid to nucleophilic heteroatom on a substrate by UDP-glucuronosyltransferase (UGT) in liver
Sulfation
Transfer of sulfonate group from 3-phophoadenosine-5’-phophosulfate (PAPS) to an available group on substrate catalyzed by cytosolic sulfotransferases (SULT)
Glutathione conjugation
Catalyzed by glutathione transferases (GST) in multiple cellular compartments
Acetylation
transfer of acetyl group from co-factor acetyl co-enzyme A to amino group on substrate, catalyzed by N-acetyltransferases.
Methylation
Methyl group from S-adenosylmethionine to electron rich (O, N, S) heteroatom. Usually decreases water solubility
Amino acid conjugation
xeno carboxylic acid to amino group of AA or xeno aromatic hydroxylamine with AA carboxylic acid
