Alprazolam hydroxylation by mouse liver microsomes in vitro: the effect of age and phenobarbital induction.
The effects of age on hepatic microsomal enzyme induction were studied in male CD-1 mice. Six week old and 1 year old animals were treated with either phenobarbital (80 mg kg-1) or saline once daily for 3d. Twenty-four hours after the last treatment, animals were sacrificed and livers were harvested. Hepatic microsomal fractions were isolated and incubated with alprazolam, a triazolobenzodiazepine metabolized by cytochrome P-450-3A isoforms in humans. Metabolites were identified and quantitated by HPLC. All microsomal preparations produced two principal metabolites (alpha-OH- and 4-OH-alprazolam) while microsomes from phenobarbital-treated animals also produced a third metabolite (alpha, 4-dihydroxyalprazolam). Vmax, K(m), and intrinsic clearance (Vmax/K(m) ratio) for both alpha-OH- and 4-OH-alprazolam in the saline-treated control animals were not significantly different between age groups. Vmax and intrinsic clearance for both metabolites were more than three times greater in phenobarbital-treated animals than in the control mice (p < 0.001). Age did not influence the extent of induction, and both pathways were induced to approximately an equal extent. Thus the present in vitro study of liver microsomal preparations from male CD-1 mice does not delineate a mechanism for impaired alprazolam clearance in aging organisms in vivo. There is no evidence that age alters susceptibility to induction by phenobarbital.
Charpentier
K P
KP
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA.
von Moltke
L L
LL
Poku
J W
JW
Harmatz
J S
JS
Shader
R I
RI
Greenblatt
D J
DJ
D000375:Aging / Q000378:metabolism*; D000525:Alprazolam / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital; D000525:Alprazolam