Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype

Abstract

Aims: To investigate the pharmacokinetics of lornoxicam and the relationship with CYP2C9 polymorphism in healthy Chinese subjects.

Methods: A single oral dose of 8 mg lornoxicam was administered to 18 healthy Chinese male subjects. Plasma was sampled for 24 h post dose, and plasma concentrations of lornoxicam were measured using a validated LC/MS/MS method. CYP2C9 genotype was determined by polymerase chain reaction-based restriction fragment length polymorphism or by direct sequencing of the coding region of the CYP2C9 gene.

Results: Of the 18 subjects, one subject was found to be a very poor metabolizer of lornoxicam with a long t(1/2) of 106 h, a low CL/F of 0.71 ml min(-1), and a high AUC(0-infinity) of 187.6 microg ml(-1) h. Genotyping studies revealed that this subject was heterozygous for CYP2C9*3 and a new variant CYP2C9 allele. Of the other 17 subjects, 13 were *1/*1 carriers, three were *1/*3 carriers, and one was a *1/*2 carrier. Mean AUC(0-infinity) values (95% confidence intervals) of lornoxicam were 9.25 (6.55, 11.95) vs. 4.75 (3.55, 5.95) microg ml(-1) h in *1 heterozygotes vs.*1 homozygotes, and mean CL/F values were 14.8 (10.2, 19.4) vs. 32.9 (24.5, 41.3) ml min(-1), respectively (P < 0.05 for both AUC and CL/F).

Conclusions: The results show that the pharmacokinetics of lornoxicam are dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs the oral clearance of lornoxicam.

Figure 1

Plasma concentration–time curves of lornoxicam in CYP2C9*1 homozygotes (□) (n = 13), CYP2C9*1 heterozygotes (▵) (n = 4), and subject 14 (♦) after a single oral dose of 8 mg lornoxicam