Multiple inhibition mechanisms and prediction of drug-drug interactions: status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions.
OBJECTIVE
To assess the consequences of multiple inhibitors and differential inhibition mechanisms on the prediction of 12 gemfibrozil drug-drug interactions (DDIs). In addition, qualitative zoning of transporter-related gemfibrozil and cyclosporine DDIs was investigated.


METHODS
The effect of gemfibrozil and its acyl-glucuronide on different enzymes was incorporated into a metabolic prediction model. The impact of CYP2C8 time-dependent inhibition by gemfibrozil acyl-glucuronide was assessed using repaglinide, cerivastatin, loperamide, rosiglitazone and pioglitazone DDIs. Gemfibrozil and cyclosporine inhibition data obtained in human embryonic kidney cells expressing OATP1B1 and hepatic input concentration ([I]in) were used for qualitative zoning of 14 transporter-mediated DDIs.


RESULTS
Incorporation of time-dependent inhibition by gemfibrozil glucuronide showed no significant improvement in the prediction, as CYP2C8 contributed <65% to the overall elimination of the victim drugs investigated. Qualitative zoning of OATP1B1 DDIs resulted in no false negative predictions; yet the magnitude of observed interactions was significantly over-predicted.


CONCLUSIONS
Time-dependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly (>80%) via CYP2C8. Qualitative zoning of OATP1B1 inhibitors based on [I]in/K (i) is valid in drug screening to avoid false negatives. Refinement of the transporter model by incorporating the fraction of drug transported by a particular transporter is recommended.
Hinton
Laura K
LK
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Galetin
Aleksandra
A
Houston
J Brian
JB
D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics; D065727:Cytochrome P-450 CYP2C8; D016208:Databases, Factual; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015248:Gemfibrozil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics; D007700:Kinetics; D011237:Predictive Value of Tests
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D020719:Glucuronides; D000960:Hypolipidemic Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil