Phenacetin O-deethylation by human liver microsomes in vitro : inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine

• Published in: Psychopharmacologia 1996-12, Vol.128 (4), p.398-407
• Main Authors: VON MOLTKE, L. L, GREENBLATT, D. J, SU XIANG DUAN, SCHMIDER, J, KUDCHADKER, L, FOGELMAN, S. M, HARMATZ, J. S, SHADER, R. I
• Format: Article
• Language: English
• Subjects: Antidepressive Agents, Second-Generation - pharmacology; Biological and medical sciences; Biotransformation - drug effects; Cyclohexanols - pharmacology; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Humans; Medical sciences; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Neuropharmacology; Pharmacology. Drug treatments; Phenacetin - metabolism; Piperazines; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Serotonin Uptake Inhibitors - pharmacology; Triazoles - pharmacology; Venlafaxine Hydrochloride
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s002130050149

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.