Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications

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.