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

Biochem Pharmacol. 1989 Dec 15;38(24):4359-65. doi: 10.1016/0006-2952(89)90643-6.


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 microM whereas the dissociation constant of the enzyme-inhibitor complex (Ki) was 0.11 microM. In contrast, 7-ethoxyresorufin O-deethylase activity (mediated by P-450c) in beta-naphthoflavone-induced rat hepatic microsomes was inhibited to a lesser extent (Ki = 2.4 microM) in relation to the Ks value (0.5 microM). Spectral studies indicated that the efficiency of thioridazine binding in phenobarbital-induced microsomes was about 25-fold greater than in microsomes from beta-naphthoflavone-induced rat liver. This finding is consistent with the relative capacity of thioridazine to inhibit oxidase activities catalyzed 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 6 beta- and 16 beta-hydroxylations of androst-4-ene-3,17-dione in hepatic microsomes from untreated rats were inhibited to a similar extent (I50S = 52 and 43 microM, respectively). The 7 alpha- and 16 alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP2B1
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / metabolism
  • Male
  • Microsomes, Liver / enzymology*
  • Oxidoreductases / antagonists & inhibitors*
  • Rats
  • Rats, Inbred Strains
  • Thioridazine / metabolism
  • Thioridazine / pharmacology*


  • Cytochrome P-450 Enzyme Inhibitors
  • Isoenzymes
  • Cytochrome P-450 Enzyme System
  • Oxidoreductases
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP2B1
  • Thioridazine