The triazolobenzodiazepine
alprazolam is biotransformed by hepatic microsomal oxidation, yielding two hydroxylated metabolites (4-hydroxy- and a-hydroxy-alprazolam) as the principal metabolic products. Both metabolites have lower
benzodiazepine receptor affinity than the parent compound and at steady state appear in plasma at concentrations considerably lower than intact
alprazolam. Thus, clinical activity during treatment with
alprazolam is essentially entirely attributable to intact
alprazolam. The
cytochrome P450 IIIA subfamily appears to mediate
alprazolam metabolism in humans. This
cytochrome subfamily is not subject to variation due to genetic polymorphism.
Ketoconazole,
cimetidine,
macrolide antibiotics, and
serotonin-reuptake-inhibitor antidepressants impair
alprazolam biotransformation in vitro. Reduced clearance of
alprazolam in vivo has been demonstrated for drugs in this group that have been studied in humans; for those not yet studied, impaired
alprazolam clearance should be anticipated during coadministration. Studies of plasma
alprazolam concentration versus clinical response during short-term treatment of
panic disorder indicate that therapeutic response at steady-state plasma levels of 20 to 40 ng/mL is significantly greater than at levels less than 20 ng/mL. Substantial additional benefit from plasma levels greater than 40 ng/mL is not consistently demonstrated. However, side effects attributable to
benzodiazepine agonist activity (e.g., drowsiness, sedation) increase in frequency with increasing steady-state plasma levels. Concentration-response data indicate that monitoring of
alprazolam plasma levels can be of considerable clinical value during treatment of
panic disorder.