Induction of hepatic cytochrome P450 2B and P450 3A isozymes in rats by zolazepam, a constituent of Telazol.

Telazol, a 1:1 combination of tiletamine HCl and zolazepam HCl, is an anesthetic and immobilizing agent that is capable of inducing cytochrome P450 (CYP) 2B isozymes in rats. The primary goal of the present study was to determine the constituent of Telazol responsible for the enzyme induction. A secondary goal was to compare the effects produced by Telazol and its constituents with those elicited by sodium phenobarbital (PB) using the same dosing regimen. Adult male Long Evans rats were given a single i.p. injection of tiletamine or zolazepam at a dose of 60 mg/kg, Telazol at a dose of 120 mg/kg, PB at a dose of 60 and 120 mg/kg, or vehicle at a dose of 1 mL/kg. Animals were killed 24 hr later, and hepatic microsomes were prepared. Treatment with zolazepam and Telazol increased microsomal benzyloxyresorufin O-dealkylase (BROD) activity by approximately 9- and 15-fold, respectively, and increased microsomal testosterone 16 beta-hydroxylase activity by 5- and 8-fold, respectively. Treatment with tiletamine had a slight, but insignificant, effect on CYP-mediated enzyme activities. In comparison, BROD and testosterone 16 beta-hydroxylase activities were increased by 22- and 13-fold, respectively, after treatment with PB at a dose of 60 mg/kg. Densitometric quantitation of immunoblots revealed that the hepatic CYP2B content was elevated by approximately 15-, 22-, and 25-fold, and the hepatic CYP3A content was increased by 2-, 2-, and 8-fold after treatment with zolazepam, Telazol, and PB, respectively. In contrast, levels of CYP1A1 and CYP2E1 were unaltered after treatment. In summary, the results indicate that zolazepam was the constituent primarily responsible for the inductive effect of Telazol, and the pattern of enzyme induction produced by zolazepam and Telazol was similar to, but weaker than that elicited by PB at a similar dosing regimen.