Stereoselective interaction between the CYP2C8 inhibitor gemfibrozil and racemic ibuprofen.
OBJECTIVE
Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers.


METHODS
In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured.


RESULTS
Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC(0-infinity)) of R-ibuprofen by 34% (range -10 to 67%; P < 0.001). The elimination half-lives (t (1/2)) of R- and S-ibuprofen were increased by 54 and 34% (range 11-162% and 16-85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC(0-infinity) ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil (P < 0.001).


CONCLUSIONS
Gemfibrozil moderately increases the AUC(0-infinity) of R-ibuprofen and prolongs its t (1/2), indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t (1/2) of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance.
Tornio
Aleksi
A
Department of Clinical Pharmacology, University of Helsinki, Haartmaninkatu 4, 00290, Helsinki, Finland.
Niemi
Mikko
M
Neuvonen
Pertti J
PJ
Backman
Janne T
JT
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007052:Ibuprofen / Q000493:pharmacokinetics*; D008297:Male; D013237:Stereoisomerism; D013379:Substrate Specificity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D015248:Gemfibrozil; D007052:Ibuprofen