In vitro metabolism of the antianxiety drug buspirone as a predictor of its metabolism in vivo.

1. Metabolism of the antianxiety drug buspirone was studied by in vitro incubations with rat liver microsomes and hepatocytes. Metabolites were isolated and purified by h.p.l.c. The purified metabolites were identified by co-elution on h.p.l.c. with authentic standards and by g.l.c.-electron impact mass spectrometry of their trimethylsilyl (TMS) derivatives. 2. Five metabolites of buspirone were identified in the microsomal incubates and seven in the hepatocyte incubates. The major metabolites arose from aromatic hydroxylation at C-5, N-dealkylation of the butyl chain, and hydroxylation at C-6' and C-3' on the azaspirodecanedione moiety. 3. Metabolism of buspirone by rat liver microsomes was NADPH-dependent and was completely inhibited by cytochrome P-450 inhibitors SKF-525A and metyrapone. 4. Metabolites of buspirone formed in vitro were good predictors of the primary metabolites formed in vivo. 5. Hepatocytes and phenobarbital-induced rat liver microsomes were better predictors of in vivo metabolism of buspirone than non-induced rat liver microsomes. These in vitro systems should provide excellent models for studying the metabolism of other azaspirodecanedione-containing drugs.