Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam in Brazilians

Background Piroxicam (P), a widely prescribed NSAID, is eliminated by hydroxylation catalyzed by CYP2C9 enzyme, which is encoded by the polymorphic CYP2C9 gene. Methods Single oral doses (20 mg) of P were given to healthy, adult Brazilian volunteers with distinct CYP2C9 genotypes. The plasma P concentration and the P‐induced changes in the activity of cyclooxygenase 1 (COX‐1; ex‐vivo formation of tromboxane B 2 in blood) were measured from zero to 240h. Results P′s oral CL/F was significantly reduced, and both AUC and t 1/2 were increased in carriers of variant alleles *2 and *3 in heterozygosis or homozygosis. There was no difference in these pharmacokinetic parameters between genotypes *1/*2 and *1/*3 . C max was not affected by CYP2C9 genotype. (see Table) The AUC for the inhibitory effect of P on the activity of COX‐1, expressed relative to the pre‐dosing value (units.h) increased with the number of variant CYP2C9 alleles, from 110± 23 ( *1/*1 , n= 5) to 172± 44 (combined *1/*2 and *1/*3 , n =12) and to 208 ‐ 223 (combined *2/*2 and *3/*3 , n =2). Conclusion We confirmed our previous observation with tenoxicam that both the variant alleles CYP2C9*2 and *3 significantly influence the pharmacokinetics of oxicam NSAIDs. We also show that both alleles *2 and *3 are associated with the intensity of the inhibitory effect of P on COX‐1. Clinical Pharmacology & Therapeutics (2005) 77 , P62–P62; doi: 10.1016/j.clpt.2004.12.127 Pharmacokinetics of piroxicam in healthy BraziliansParameter *1/*1 (n = 14) *1/*2 ( n = 9 ) *1/*3 (n = 10) *2/*2 (n = 1) *2/*3 (n = 1) *3/*3 (n = 1)C max (mgL −1 ) 2.4 ± 0.7 2.2 ± 0.4 2.5 ± 0.4 1.6 1.9 2.6 AUC 0‐240h (mg.L −1 ) 136 ± 34 220 ± 77 221 ± 67 197 186 501 CL/F (L.h −1 ) 0.14 ± 0.03 0.09 ± 0.03 0.08 ± 0.02 0.09 0.07 0.01 t 1/2 (h) 40.3 ± 9.8 72.8 ± 19.9 80.1 ± 24.7 94.6 118.5 674.1