The prediction of in vivo drug-drug interactions from in vitro enzyme inhibition parameters remains challenging, particularly when time-dependent inhibition occurs. This study was designed to examine the accuracy of in vitro-derived parameters for the prediction of inhibition of CYP3A by erythromycin (ERY). Chronically cannulated rats were used to estimate the reduction in in vivo and in vitro intrinsic clearance (CLint) of midazolam (MDZ) after single and multiple doses of ERY; in vitro recovery of CLint was determined at 1, 2, 3, and 4 days after discontinuation of ERY. Enzyme inhibition parameters (kinact, KI, and K i) of ERY were estimated in vitro by using untreated rat liver microsomes. In vivo enzyme kinetic analysis indicated that single and multiple doses of ERY (150 mg/kg i.v. infusion over 4 h) reduced MDZ CLint by reversible and irreversible mechanisms, respectively. CYP3A inactivation after multiple doses of ERY treatment reflected metabolic intermediate complex formation without a significant change in hepatic CYP3A2 mRNA. A physiologically based pharmacokinetic model of the interaction between ERY and MDZ predicted a 2.6-fold decrease in CYP3A activity after repeated ERY treatment using in vitro-estimated enzyme inhibition parameters and in vivo degradation half-life of the enzyme (20 ± 6 h). The observed -fold decreases were 2.3-fold and 2.1-fold for the in vitro-estimated CYP3A activity and the in vivo CL int, respectively. This study demonstrates that in vivo DDIs are predictable from in vitro data when the appropriate model and parameter estimates are available.
ASJC Scopus subject areas
- Pharmaceutical Science