Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2

Objective According to in vitro data, the polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) may be the major S ‐ibuprofen hydroxylase. In humans, there are 2 variants of CYP2C9 with a high population frequency. We studied their impact on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Methods Kinetics of an oral dose of 600 mg racemic ibuprofen were studied in 21 healthy volunteers with all combinations of the CYP2C9 variants * 2 (arginine144cysteine) and * 3 (isoleucine359leucine). Blood concentrations of racemic ibuprofen and of S ‐(+)‐ibuprofen and R ‐(−)‐ibuprofen were measured by HPLC, and thromboxane B 2 and prostaglandin E 2 were measured with use of an enzyme immunoassay. Data were evaluated witha population pharmacokinetic model that integrated pharmacogenetic information. Results The pharmacokinetics of racemic and of S ‐ibuprofen depended on the CYP2C9 isoleucine359leucine amino acid polymorphism: population mean S ‐ibuprofen clearances were 3.25 L/h (95% confidence interval [CI], 2.84 to 3.73), 2.38L/h (95% CI, 2.09 to 2.73), and 1.52 L/h (95% CI, 1.33 to 1.74) in carriersof the CYP2C9 genotypes * 1/ * 1, * 1/ * 3 , and * 3/ * 3 , respectively. The CYP2C9 variant * 2 exhibited no significant effect. Ex vivo formation of thromboxane B 2 , reflecting cyclooxygenase type 1 inhibition, depended significantly on the CYP2C9 polymorphism. The maximal inhibition ofthromboxane B 2 formation and the area under the effect‐time curve were larger in carriers of the slow CYP2C9 genotypes * 1/ * 3, * 2/ * 3 , and * 3/ * 3 than in * 1/ * 1 carriers; the same trend was observed for prostaglandin E 2 , reflecting cyclooxygenase type 2 inhibition. Conclusions The reduced S ‐ibuprofen total clearance accompanied by increased pharmacodynamic activity may have medical impact in patients receiving ibuprofen. Clinical Pharmacology & Therapeutics (2002) 72 , 62–75; doi: 10.1067/mcp.2002.125726