Inhibition of hepatic drug metabolism by phenothiazine tranquilizers: quantitative structure-activity relationships and selective inhibition of cytochrome P-450 isoform-specific activities.

Twelve phenothiazine tranquilizers were investigated for the capacity to inhibit rat hepatic microsomal cytochrome P-450 (P-450) isoform-specific drug oxidation in vitro. All congeners were substituted in the 2-(carbocyclic) and 10- (thiazinyl nitrogen of the thiazine ring) positions. Cytochrome P-450 PB-B-mediated 7-pentylresorufin O-depentylase and P-450 BNF-B-mediated 7-ethylresorufin O-deethylase activities were effectively inhibited by most of the compounds. Structure-activity correlations revealed the apparent importance of the lipophilicity of the 2-substituent, and the negative effect of flexibility in the 10-position substituent, on anti-P-450 PB-B potency. On the other hand, inhibition of P-450 BNF-B activity was promoted by bulkiness and branching within the 10-substituent and the shape/bulk of the 2-group. From this analysis it is likely that the active site of P-450 PB-B is relatively small with at least one lipophilic region that may be involved in substrate and inhibitor binding. The active site of P-450 BNF-B is relatively large, and steric properties, rather than lipophilic character, appear to determine inhibition by phenothiazines. Derivatives with piperidinyl and piperazinyl ring systems in the 10-position were relatively active inhibitors of P-450 PCN-E (or an immunochemically related form of P-450) that catalyzes androst-4-ene-3,17-dione 6 beta-hydroxylation, and P-450 UT-A-mediated 16 alpha-hydroxylase activity. In contrast, steroid 7 alpha-hydroxylation (P-450 UT-F) and N-nitrosodimethylamine N-demethylation (P-450j) were refractory to inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)