The effect of midazolam administration on the pharmacokinetics of antipyrine in the rat

Abstract

1. The clearance and elimination half-lives for i.v. doses of antipyrine were determined in 6 groups of 6 male CD rats with no prior treatment, then again following 7 days treatment with graded oral doses of midazolam, and finally after 3 i.p. doses of phenobarbitone.

2. Substantial increases in clearance and decreases in half-lives were observed following phenobarbitone treatment, demonstrating that antipyrine provides a reliable index of enzyme induction.

3. After treatment with midazolam, maximal induction was seen in animals dosed at 27 or 80 mg/kg per day; an intermediate effect was found with 9 mg/kg per day and no effect at 0.2 and 1.0 mg/kg per day.

4. The results indicate that there is a substantial margin of safety between the proposed human therapeutic doses (7.5 to 15 mg/day) and the minimum effective dose that leads to enzyme induction in laboratory animals.