title: Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine.
abstract: Biotransformation of phenacetin via O-deethylation to acetaminophen, an index reaction reflecting activity of Cytochrome P450-1A2, was studied in microsomal preparations from a series of human livers. Acetaminophen formation was consistent with a double Michaelis-Menten system, with low-Km (mean Km1 = 68 microM) and high-Km (mean Km2 = 7691 microM) components. The low-K(m) enzyme accounted for an average of 96% of estimated intrinsic clearance, and was predicted to contribute more than 50% of net reaction velocity at phenacetin concentrations less than 2000 microM. Among index inhibitor probes, alpha-naphthoflavone was a highly potent inhibitor of the low-Km enzyme (Ki1 = 0.013 microM); furafylline also was a moderately active inhibitor (Ki1 = 4.4 microM), but its inhibiting potency was increased by preincubation with microsomes. Ketoconazole was a relatively weak inhibitor (Ki1 = 32 microM); quinidine and cimetidine showed minimal inhibiting activity. Among six selective serotonin reuptake inhibitor (SSRI) antidepressants, fluvoxamine was a potent inhibitor of 1A2 (mean Ki1 = 0.24 microM). The other SSRIs were more than tenfold less potent. Mean Ki1 values were: fluoxetine, 4.4 microM; norfluoxetine, 15.9 microM; sertraline, 8.8 microM; desmethylsertraline, 9.5 microM; paroxetine, 5.5 microM. The antidepressant nefazodone and four of its metabolites (meta-chloro-phenylpiperazine, two hydroxylated derivatives, and a triazoledione) were very weak inhibitors of P450-1A2. Venlafaxine and its O- and N-desmethyl metabolites showed minimal inhibitory activity.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: S X
authors.initials: SX
authors.lastname: Duan
authors.forename: J
authors.initials: J
authors.lastname: Schmider
authors.forename: L
authors.initials: L
authors.lastname: Kudchadker
authors.forename: S M
authors.initials: SM
authors.lastname: Fogelman
authors.forename: J S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D003511:Cyclohexanols / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010615:Phenacetin / Q000378:metabolism*; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D000069470:Venlafaxine Hydrochloride
chemical_list: D018687:Antidepressive Agents, Second-Generation; D003511:Cyclohexanols; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004791:Enzyme Inhibitors; D010615:Phenacetin; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D014230:Triazoles; D000069470:Venlafaxine Hydrochloride; C051752:nefazodone