Elsevier

Biochemical Pharmacology

Volume 38, Issue 24, 15 December 1989, Pages 4359-4365
Biochemical Pharmacology

In vitro inhibition of hepatic drug oxidation by thioridazine: Kinetic analysis of the inhibition of cytochrome p-450 isoform-specific reactions

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Abstract

The phenothiazine tranquilizer thioridazine has been associated with drug interactions in man. This study investigated the capacity of the drug to inhibit hepatic drug oxidations mediated by cytochromes P-450 (P-450) in microsomes in vitro. Thioridazine was a potent linear mixed-type inhibitor of P-450b-dependent 7-pentoxyresorufin O-depentylase activity in phenobarbital-induced rat liver. The kinetic analysis revealed the enzyme-substrate dissociation constant (Ks) to be 1.6 μM whereas the dissociation constant of the enzyme-inhibitor complex (Ki) was 0.11 μM. In contrast, 7-ethoxyresorufin O-deethylase activity (mediated by P-450c) in β-naphthoflavone-induced rat hepatic microsomes was inhibited to a lesser extent (Ki = 2.4 μM) in relation to the Ks value (0.5 μM). Spectral studies indicated that the efficiency of thioridazine binding in phenobarbital-induced microsomes was about 25-fold greater than in microsomes from β-naphthoflavone-induced rat liver. This finding is consistent with the relative capacity of thioridazine to inhibit oxidase activities catalysed by P-450b and P-450c. Mixed-function oxidase activities catalysed by other P-450s were also inhibited by thioridazine, although to a lesser extent than those catalysed by forms b and c. Thus, the 6β- and 16β-hydroxylations of androst-4-ene-3, 17-dione in hepatic microsomes from untreated rats were inhibited to a similar extent (I50S = 52 and 43 μM, respectively). The 7α- and 16α-hydroxylase pathways were approximately only half as susceptible to inhibition by thioridazine. These findings demonstrate the capacity of thioridazine to inhibit a range of P-450-dependent drug oxidations, with those catalysed by forms b and c most susceptible. The present study strongly suggests that drug interactions elicited by thioridazine are most likely a consequence of inhibitory interactions with P-450 enzymes.

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