CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians

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Abstract

Objective

Cytochrome P450 (CYP) 2C9, the product of the polymorphic gene CYP2C9, provides the major catabolic pathway for several anti-inflammatory drugs, including tenoxicam. Our objectives were (1) to determine the frequency of 2 common CYP2C9 variant alleles (*2 and *3) in the Brazilian population and (2) to evaluate the effects of these polymorphisms on the pharmacokinetics of tenoxicam.

Methods

Polymerase chain reaction-restriction fragment length polymorphism methods were used to identify CYP2C9*2 and CYP2C9*3 in 331 healthy Brazilians, classified as white (n = 136), black (n = 77), or intermediate (n = 118). A validated HPLC procedure was used for measuring the plasma concentrations of tenoxicam, after single oral doses of 20 mg, administered to 21 individuals with CYP2C9*1/*1 (n = 12), CYP2C9*1/*2 (n = 4), or CYP2C9*1/*3 genotypes (n = 5), confirmed by deoxyribonucleic acid sequencing. A 2-compartment pharmacokinetic model was used for fitting the plasma concentration versus time data, and the individual model descriptive parameters were used to simulate the plasma tenoxicam concentrations during repeated dosing for 7 consecutive days.

Results

The frequencies of CYP2C9*1, CYP2C9*2, and CYP2C9*3 in the study population were 0.849, 0.086, and 0.065, respectively. The distribution of CYP2C9 alleles differed across the Brazilian color groups (P = .016), with the frequencies of the variant alleles being 2.5 to 3 times lower in black Brazilians than in white Brazilians (P = .003). After a single dose of tenoxicam, the area under the plasma concentration-time curve (AUC) from time 0 to infinity and the oral clearance of tenoxicam were 190 ± 48 μg · mL−1 · h and 113 ± 30 mL · h−1, respectively, in wild-type homozygous subjects (CYP2C9*1/*1), as compared with 261 ± 14 μg ·mL−1 · h (P = .013) and 77 ± 4mL · h−1 (P = .036), respectively, in CYP2C9*1/*2 heterozygous subjects and 335 ± 126 μg · mL−1 ·h−1 (P = .003) and 67 ± 23 mL · h−1 (P = .008) in CYP2C9*1/*3, respectively, heterozygous subjects. After 7 simulated daily doses, significant differences were observed between CYP2C9*1/*1 and CYP2C9*1/*3 individuals in relation to the minimum plasma (trough) tenoxicam concentration (Cmin, 5.2 ± 1.3 μg · mL−1 versus 7.6 ± 2.6 μg ·mL−1; P = .021), maximum tenoxicam plasma concentration (Cmax, 7.4 ± 1.9 μg · mL−1 versus 10.5 ± 3.0 μg · mL−1; P = .020), and 24-hour AUC (152 ± 39 μg ·mL−1 · h versus 219 ± 72 μg · mL−1 · h). No significant differences were observed in Cmin, Cmax, or AUC between CYP2C9*1/*2 and either CYP2C9*1/*1 or CYP2C9*1/*3 individuals.

Conclusion

The allelic and genotypic frequencies of CYP2C9*1, *2, and *3 in white and black Brazilians are similar to those reported for other white (Caucasian) and black (African and African American) populations, respectively. Heterozygosis for CYP2C9*3, and to a lesser degree CYP2C9*2, increases the exposure to tenoxicam during single and repeated doses.

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