Received for publication September 24, 2007.
Revised March 11, 2008.
Accepted for publication March 31, 2008.

PREDICTION OF PHARMACOKINETIC DRUG-DRUG INTERACTIONS USING HUMAN HEPATOCYTE SUSPENSION IN PLASMA - PART III. IN VITRO-IN VIVO CORRELATION WITH FLUCONAZOLE

Abstract

While ketoconazole is often used to study the worst-case scenario for clinical pharmacokinetic drug-drug interactions (DDIs) for drugs that are primarily metabolized by CYP3A4, fluconazole is considered to be a moderate inhibitor of CYP3A4, providing assessment of moderate-case scenario of CYP3A based DDIs. Fluconazole is also a moderate inhibitor of CYP2C9 and 2C19. For predicting the clinical DDIs, using conventional approaches, determining the in vivo inhibitor concentration at the enzymatic site [I], a critical parameter, is still not practical. In our previous study (Lu et al., 2007), a novel method involving hepatocyte suspension in plasma was used to circumvent the need to determine the elusive [I] value. In this study, the CYP1A2, 2C9, 2C19, 2D6, and 3A4 activities remaining in the presence of fluconazole were determined in human hepatocytes suspended in human plasma, covering a range of fluconazole clinical plasma concentrations (Cavg , Cmax). Since the protein binding effect of fluconazole is expected to be close to that in vivo, the inhibition observed in vitro will be similar to that in vivo. This inhibition information was then applied to the CYP phenotypic data to predict DDIs. Using the available CYP phenotypic information on theophylline, tolbutamide, omeprazole, S-warfarin, phenytoin, cyclosporine, and midazolam, and that determined in here for sirolimus and tacrolimus, the predictions for AUC increases for most of these drugs in the presence of fluconazole were remarkably similar, within 35%, to the observed clinical values. This study proves the general applicability of our approach using human hepatocyte incubation in human plasma to predict DDIs.

Key words: CYP inhibition, drug-drug interactions, enzyme inhibitors, hepatocytes, human CYP enzymes, in vitro-in vivo prediction, inhibition, isolated hepatocytes