Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam.
OBJECTIVE
Our objective was to evaluate the influence of cytochrome P450 (CYP) 2C9 polymorphisms on the pharmacokinetics and pharmacodynamics of the nonsteroidal anti-inflammatory drug piroxicam.


METHODS
Thirty-five healthy subjects with CYP2C9 genotypes *1/*1 (n=17), *1/*2 (n=9), and *1/*3 (n=9) received a single oral dose of piroxicam (20 mg). Blood samples were collected at various time points up to 240 hours for measurements of the concentrations of piroxicam and thromboxane B2 (TXB2).


RESULTS
Piroxicam's area under the plasma concentration-time curve from time 0 to infinity and oral clearance corrected for body weight were 154+/-37 microg.mL-1.h and 2.0+/-0.5 mL.h-1.kg-1, respectively, in CYP2C9*1/*1 individuals, as compared with 256+/-97 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*2 individuals and 259+/- 95 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*3 individuals. There were no significant differences between CYP2C9*1/*2 and CYP2C 9*1/*3 individuals in these pharmacokinetic parameters (P=.95 for area under the plasma concentration-time curve from time 0 to infinity and P=.94 for oral clearance corrected for body weight). The formation of TXB2, reflecting cyclooxygenase type 1 activity, showed significant differences in the area above the effect-time curves (expressed as percent of baseline TXB2.h) between CYP2C9*1/*1 (10,190 +/- 2632) and either CYP2C9*1/*2 (19,255+/-1,291 [P=.00003]) or CYP2C9*1/*3 (18,241+/- 2397 [P=.00003]). The minimum serum TXB2 concentration, however, did not differ among the different genotypes (P=.32, ANOVA).


CONCLUSIONS
Piroxicam's oral clearance was impaired and its inhibitory effect on cyclooxygenase 1 activity was increased in CYP2C9*1/*2 or CYP2C9*1/*3 individuals, as compared with CYP2C 9*1 homozygous individuals.
Perini
Jamila A
JA
Divisão de Farmacologia, Instituto Nacional de Câncer, and Departamento de Farmacologia Básica e Clínica, Universidade Federal do Rio de Janeiro, Brazil.
Vianna-Jorge
Rosane
R
Brogliato
Ariane R
AR
Suarez-Kurtz
Guilherme
G
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D051545:Cyclooxygenase 1; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008657:Metabolic Clearance Rate; D010894:Piroxicam / Q000493:pharmacokinetics / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013929:Thromboxane B2 / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008565:Membrane Proteins; D010894:Piroxicam; D013929:Thromboxane B2; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases