title: Alprazolam metabolism in vitro: studies of human, monkey, mouse, and rat liver microsomes.
abstract: Biotransformation of the triazolobenzodiazepine alprazolam (ALP) was studied in vitro using hepatic microsomal preparations from human, monkey, mouse, and rat liver tissue. Two principal hydroxylated metabolites were identified: 4-hydroxy- and alpha-hydroxy-alprazolam (4-OH-ALP and alpha-OH-ALP). In all species, rates of 4-OH-ALP formation exceeded those of alpha-OH-ALP. In human liver microsomes, ratios of 4-OH-ALP/alpha-OH-ALP reaction velocities calculated at clinically relevant plasma concentrations of ALP ranged from 7 to 17, qualitatively consistent with, but numerically larger than, the ratio of the plasma levels of the two metabolites during clinical use of ALP in humans. Km values for both 4-OH-ALP (170-305 microM) and alpha-OH-ALP (63-441 microM) considerably exceeded the usual maximum plasma concentration observed in humans (200 ng/ml, 0.65 microM), consistent with the linear (dose-independent) pharmacokinetic characteristics of ALP observed in humans. Thus formation of 4-OH-ALP via hydroxylation is the major route of ALP metabolism. This pathway is probably mediated by the cytochrome P-450-3A subfamily. Factors that impair the activity of this cytochrome subtype are likely to impair clearance of ALP in vivo.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111.
authors.forename: L L
authors.initials: LL
authors.lastname: von Moltke
authors.forename: D J
authors.initials: DJ
authors.lastname: Greenblatt
authors.forename: J S
authors.initials: JS
authors.lastname: Harmatz
authors.forename: R I
authors.initials: RI
authors.lastname: Shader
mesh_terms: D000328:Adult; D000368:Aged; D000525:Alprazolam / Q000378:metabolism* / Q000493:pharmacokinetics*; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008251:Macaca; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
chemical_list: D000525:Alprazolam