Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles.

Abstract

To determine the effect of oral administration of low doses of pentobarbital on cytochrome P450 (CYP) isoforms and CYP-mediated reactions in immature Beagles. 42 immature (12-week-old) Beagles. Dogs were grouped and treated orally as follows for 8 weeks: low-dose pentobarbital (50 microg/d; 4 males, 4 females), mid-dose pentobarbital (150 microg/d; 4 males, 4 females), high-dose pentobarbital (500 microg/d; 4 males, 4 females), positive-pentobarbital control (10 mg/kg/d; 2 males, 2 females), positive-phenobarbital control (10 mg/kg/d; 2 males, 2 females), and negative control (saline 10.9% NaCl] solution; 5 males, 5 females). Serum biochemical and hematologic values were monitored. On necropsy examination, organ weights were determined, and histologic evaluation of tissue sections of liver, kidney, small intestine, testes, epididymis, and ovaries was performed. Hepatic and intestinal drug-metabolizing enzyme activities were measured, and relative amounts of CYP isoforms were determined by western blot analysis. The amount of a hepatic CYP2A-related isoform in dogs from the high-dose pentobarbital treatment group was twice that of dogs from the negative control group. CYP2C was not detectable in small intestinal mucosa of dogs from the negative control group; measurable amounts of CYP2C were found in dogs from the various (low-, mid-, and high-dose) pentobarbital treatment groups and from positive-pentobarbital and positive phenobarbital control groups. Several CYP-mediated reactions increased in a dose-dependent manner. The lowest calculated effective dose of pentobarbital ranged from 200 to 450 microg/d. Several CYP isoforms and their associated reactions were induced in dogs by oral administration of low amounts of pentobarbital.