Lack of In Vivo Correlation Between Indinavir and Saquinavir Exposure and Cytochrome P450 3A Phenotype as Assessed with Oral Midazolam as a Phenotype Probe

Abstract

Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.

Quantitative Correlations Among CYP3A Sensitive Substrates and Inhibitors:Literature Analysis

“…However, a body of recent literature indicates that the notion of interchangeability of CYP3A substrates is far from resolved [2][3][4][5][6][7]. Indeed, we tested the assumption of substrate independence using a large pool of inhibition studies and found an appreciable number of exceptions.…”