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 with a 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), 2.38 L/h (95% CI, 2.09 to 2.73), and 1.52 L/h (95% CI, 1.33 to 1.74) in carriers of 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 of thromboxane 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.
Kirchheiner
Julia
J
Institute of Clinical Pharmacology, Charité, Humboldt University, Berlin, Germany.
Meineke
Ingolf
I
Freytag
Georg
G
Meisel
Christian
C
Roots
Ivar
I
Brockmöller
Jürgen
J
D000328:Adult; D000465:Algorithms; D000483:Alleles; D019943:Amino Acid Substitution; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D013237:Stereoisomerism; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D013929:Thromboxane B2 / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D013929:Thromboxane B2; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D039181:Steroid 16-alpha-Hydroxylase; D015232:Dinoprostone; D007052:Ibuprofen