CYP2C19 inhibition: the impact of substrate probe selection on in vitro inhibition profiles.
Understanding the potential for cytochrome P450 (P450)-mediated drug-drug interactions is a critical part of the drug discovery process. Factors such as nonspecific binding, atypical kinetics, poor effector solubility, and varying ratios of accessory proteins may alter the kinetic behavior of an enzyme and subsequently confound the extrapolation of in vitro data to the human situation. The architecture of the P450 active site and the presence of multiple binding regions within the active site may also confound in vitro-in vivo extrapolation, as inhibition profiles may be dependent on a specific inhibitor-substrate interaction. In these studies, the inhibition profiles of a set of 24 inhibitors were paneled against the CYP2C19 substrate probes (S)-mephenytoin, (R)-omeprazole, (S)-omeprazole, and (S)-fluoxetine, on the basis of their inclusion in recent U.S. Food and Drug Administration guidance for in vitro drug-drug interactions with CYP2C19. (S)-Mephenytoin was inhibited an average of 5.6-fold more potently than (R)- or (S)-omeprazole and 9.2-fold more potently than (S)-fluoxetine. Hierarchical clustering of the inhibition data suggested three substrate probe groupings, with (S)-mephenytoin exhibiting the largest difference from the rest of the substrate probes, (S)-fluoxetine exhibiting less difference from (S)-mephenytoin and the omeprazoles and (R)- and (S)-omeprazole exhibiting minimal differences from each other. Predictions of in vivo inhibition potency based on the in vitro data suggest that most drug-drug interactions will be identified by either (S)-mephenytoin or omeprazole, although the expected magnitude of the interaction may vary depending on the chosen substrate probe.
Foti
Robert S
RS
Pharmacokinetics and Drug Metabolism, Amgen, Inc., Seattle, Washington 98119, USA.
Wahlstrom
Jan L
JL
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016000:Cluster Analysis; D065731:Cytochrome P-450 CYP2C19; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005473:Fluoxetine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008617:Mephenytoin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009853:Omeprazole / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D005473:Fluoxetine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin