Time course of enzyme induction in humans: effect of pentobarbital on nortriptyline metabolism.
To study the effect of induction we gave six male volunteers 10 mg nortriptyline three times a day for 4 weeks and 0.2 gm pentobarbital on days 8 to 21. Plasma and urinary levels of nortriptyline and metabolites were measured. The rate and extent of induction of the enzyme(s) were estimated by a model with use of nortriptyline concentrations. There was a marked decrease of nortriptyline levels after 2 days of pentobarbital treatment. Total clearance of nortriptyline increased more than twofold (range, 1.6-fold to 4.1-fold). Apparent metabolic clearance by 10-hydroxylation increased markedly. The decrease in nortriptyline levels was more rapid than the increase after pentobarbital cessation, fitting with the theory of the model. The induction of nortriptyline metabolism is probably mainly the result of an increase in a non-CYP 2D6 P450 isozyme, possibly CYP 3A4 or a CYP 2C form. More knowledge of induction characteristics of drugs should lead to better predictions of decreased effects and appearance of adverse effects. The kinetic model used for analysis of our data could then be useful.
Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge Hospital, Sweden. christer.v.bahr@medklin.sos.sll.se
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von Bahr
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Steiner
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Koike
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Gabrielsson
D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000378:metabolism* / Q000652:urine; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D004790:Enzyme Induction; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000187:drug effects*; D009661:Nortriptyline / Q000097:blood / Q000378:metabolism* / Q000652:urine; D010424:Pentobarbital / Q000494:pharmacology*; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D018757:GABA Modulators; D003577:Cytochrome P-450 Enzyme System; D009661:Nortriptyline; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D010424:Pentobarbital