[The relationship between single-oral dose kinetics of alprazolam and cytochrome P4503A and cytochrome P4502C19].
To clarify the involvement of cytochrome P4503A (CYP3A) and CYP2C19 in the metabolism of alprazolam, the effects of pretreatment with erythromycin, which is an inhibitor of CYP3A and S-mephenytoin 4-hydroxylation capacity on the single-oral dose kinetics of alprazolam were studied in 12 healthy male volunteers. Six each were extensive metabolizers (EMs) and poor metabolizers (PMs) of S-mephenytoin 4-hydroxylation. Each subject received erythromycin 1,200 mg/day or placebo for 10 days in a double-blind, crossover manner. At 9 AM of day 8 alprazolam 0.8 mg was given orally, and blood samplings were performed up to 48 hours postdosing. Erythromycin treatment compared with placebo treatment increased significantly plasma alprazolam concentrations from 6 to 48 hours postdosing. Erythromycin significantly decreased the apparent oral clearance and prolonged the elimination half-life of alprazolam. No significant difference was found in plasma concentrations and pharmacokinetic parameters of alprazolam between the EM and PM groups. The present study thus suggests that CYP3A, but not CYP2C19, is involved in the metabolism of alprazolam.
Department of Neuropsychiatry, Hirosaki University Hospital, Japan.
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Yasui
D000284:Administration, Oral; D000328:Adult; D000525:Alprazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004311:Double-Blind Method; D004917:Erythromycin / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000502:physiology*
D014151:Anti-Anxiety Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000525:Alprazolam