¹Divisão de Farmacologia, Instituto Nacional de Câncer, and Departamento de Farmacologia Básica e Clínica, Universidade Federal do Rio de Janeiro

Correspondence: Guilherme Suarez-Kurtz, MD, Doct Med, Instituto Nacional de Câncer, Rua André Cavalcanti 37, Rio de Janeiro, RJ, 20231-050, Brazil E-mail: kurtz@inca.gov.br

^*This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), and Swiss Bridge Foundation.

Received 18 April 2005; Accepted 29 June 2005.

Abstract

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 g 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 CYP2C9*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).

Conclusion: 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 CYP2C9*1 homozygous individuals.