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

Abstract

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 B2 in blood) were measured from zero to 240h. Results P′s oral CL/F was significantly reduced, and both AUC and t1/2 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. Cmax 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: Pharmacokinetics of piroxicam in healthy Brazilians Parameter *1/*1 (n = 14) *1/*2 (n = 9) *1/*3 (n = 10) *2/*2 (n = 1) *2/*3 (n = 1) *3/*3 (n = 1) Cmax(mgL−1)2.4 ± 0.72.2 ± 0.42.5 ± 0.41.61.92.6AUC0‐240h(mg.L−1)136 ± 34220 ± 77221 ± 67197186501CL/F (L.h−1)0.14 ± 0.030.09 ± 0.030.08 ± 0.020.090.070.01t1/2 (h)40.3 ± 9.872.8 ± 19.980.1 ± 24.794.6118.5674.1

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Heterozygosity for CYP2C9*2 or *3 has been associated with 1.6-to 1.9-fold higher mean lornoxicam AUCs compared with those for the wild type (Zhang et al, 2005b;Liu et al, 2006). For piroxicam and tenoxicam, the AUCs after a single dose were significantly higher in Brazilian volunteers with CYP2C9*1/*2 (1.7-and 1.4-fold, respectively) and *1/*3 (1.7-and 1.8-fold, respectively) compared with those for the wild type (Vianna-Jorge et al, 2004;Perini et al, 2005). Data on the CYP2C9*3/*3 genotype are not available.…”

“…Oxicams. The oxicams are hydroxylated by CYP2C9 in vitro (Zhao et al, 1992;Leemann et al, 1993;Bonnabry et al, 1996;Takanashi et al, 2000), with lornoxicam, piroxicam, and tenoxicam being affected by CYP2C9 variants in vivo (Vianna-Jorge et al, 2004;Perini et al, 2005;Zhang et al, 2005b). In a Chinese bioequivalence study of lornoxicam, one volunteer had an AUC almost 40-fold greater than those seen in wild type subjects.…”

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

“…To date, 30 CYP2C9 allelic variants located within the coding region have been reported (http://www.imm.ki.SE/CYPalleles). In particular, the *3 allele (Ile 359 Leu), which is expressed at an allele frequency of 15% (Lee et al, 2002), results in significantly reduced oral clearance for several CYP2C9 substrates (Aithal et al, 1999;Lee et al, 2003b;Vianna-Jorge et al, 2004;Guo et al, 2005;Perini et al, 2005) and has been associated with an increased frequency of adverse events after warfarin or phenytoin administration (Kidd et al, 2001;Higashi et al, 2002).…”

Significance of pharmacogenetic testing in solution of problem of nonsteroid antirheumatic drugs administration gastro-intestinal safety

“…обнаружили сни-жение клиренса ибупрофена у здоровых доброволь-цев с генотипами CYP2C9*1/*2 и CYP2C9*1/*3 по сравнению с носителями генотипа CYP2C9*1/*1 [9]. Аналогичные изменения фармакокинетики у лиц, являющихся носителями аллельных вариантов CYP2C9*2 и CYP2C9*3, были отмечены при при-менении и других НПВП, таких как флубипрофен [10], лорноксикам [11], пироксикам [12]. В то же время U. Yasar и соавт.…”