ALPRAZOLAM PHARMACOKINETICS, METABOLISM, AND PLASMA-LEVELS - CLINICALIMPLICATIONS

The triazolobenzodiazepine alprazolam is biotransformed by hepatic mic rosomal oxidation, yielding two hydroxylated metabolites (4-hydroxy- a nd a-hydroxy-alprazolam) as the principal metabolic products. Both met abolites have lower benzodiazepine receptor affinity than the parent c ompound and at steady state appear in plasma at concentrations conside rably lower than intact alprazolam. Thus, clinical activity during tre atment with alprazolam is essentially entirely attributable to intact alprazolam. The cytochrome P450 IIIA subfamily appears to mediate alpr azolam metabolism in humans. This cytochrome subfamily is not subject to variation due to genetic polymorphism. Ketoconazole, cimetidine, ma crolide antibiotics, and serotonin-reuptake-inhibitor antidepressants impair alprazolam biotransformation in vitro. Reduced clearance of alp razolam in vivo has been demonstrated for drugs in this group that hav e been studied in humans; for those not yet studied, impaired alprazol am 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 a t steady-state plasma levels of 20 to 40 ng/mL is significantly greate r than at levels less than 20 ng/mL. Substantial additional benefit fr om plasma levels greater than 40 ng/mL is not consistently demonstrate d. However, side effects attributable to benzodiazepine agonist activi ty (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.