Pharmacological Research 59 (2009) 62–68 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Pharmacogenetic relevance of the CYP2C9*3 allele in a tenoxicam bioequivalence study performed on Spaniards A.M. Peiró a,b,∗,1 , J. Novalbos c,d,1 , P. Zapater a,b,d , R. Moreu b , R. López-Rodríguez c,d , V. Rodríguez c,d , F. Abad-Santos c,d , J.F. Horga a,b,d a Division of Pharmacology and Therapeutics, Instituto de Bioingeniería, Miguel Hernández University, Campus de San Juan, 03550 San Juan de Alicante, Alicante, Spain b Division of Clinical Pharmacology, Hospital General de Alicante, 0310 Alicante, Spain c Service of Clinical Pharmacology, Hospital Universitario de la Princesa, 28006 Madrid, Spain d Instituto Teófilo Hernando, Universidad Autónoma de Madrid, 28029 Madrid, Spain article info Article history: Accepted 26 September 2008 Keywords: CYP2C9*3 Tenoxicam Bioequivalence study Pharmacogenetic Spaniards abstract We performed a study to quantify CYP2C9 and CYP2C8 alleles influence on the variability observed in tenoxicam pharmacokinetic (PK) and implication in a bioequivalence study design performed on Spaniards. Eighteen healthy volunteers were included in an open, randomized, crossover, phase I bioe- quivalence study. Significant increases were found in CYP2C9*3 alleles vs. *1 and *2 in AUC 0–∞ (median (min–max)): 256 (230–516) vs. 150 (100–268) and 169 (124–197) g h/mL (p < 0.01) and half-life time (t1/2) 102 (79–36) vs. 56 (45–94) and 64 (60–80) h (p < 0.01). Non-significant differences were observed in C max 1.9 (1.8–2.9) vs. 2.4 (1.7–3.4), 2.5 (1.6–2.9) g/mL or in according to CYP2C8 alleles presence. CYP2C9*3 allele is associated to a longer elimination time of tenoxicam. PK parameters calculated in bioe- quivalence studies (AUC 0–∞ , t1/2) may be influenced by the presence of CYP2C9*3 allele resulting in a high variability. Thus, bioequivalence studies of tenoxicam formulations should be designed considering genotype profile. © 2008 Elsevier Ltd. All rights reserved. 1. Introduction Practitioners need assurance that switching from a brand drug product to a generic equivalent provides comparable safety and efficacy when used in a given patient. To establish bioe- quivalence, pharmacokinetic studies are conducted following the administration of the two compounds in a crossover study in vol- unteer subjects. The presence of genetic differences, i.e. single nucleotide polymorphisms (SNP) present in metabolizing enzymes can directly induce a higher intersubject pharmacokinetic variabil- ity that may condition the bioequivalence outcome. In this study we analyze the pharmacokinetic variability of tenoxicam related to its metabolism through the polymor- phic drug-metabolizing enzyme cytochrome P450 (CYP) 2C9, the major catabolic pathway of non-steroidal anti-inflammatory drugs ∗ Corresponding author at: Division of Clinical Pharmacology, Hospital General Universitario de Alicante, c/Pintor Baeza, 12. 03010 Alicante, Spain. Tel.: +34 965 93 8224; fax: +34 965 93 8226. 1 These authors contributed equally to this work. (NSAIDs). Over 50 SNPs have been described in regulatory and cod- ing regions of this gene; however, only two of them are common in Caucasians: CYP2C9*2 and CYP2C9*3 [1–4]. Also, a significant con- tribution of CYP2C8 to the metabolism of several NSAIDs drugs has been show such as diclofenac or ibuprofen as well as pacli- taxel, propofol, rosiglitazone, fluvastatin, methadone, morhphine and repaglinide [5,6]. Recently, allelic variants of CYP2C8 have also been found in Caucasians, as is the case for allele CYP2C8*3 and CYP2C8*4 [4,7,8]. Ethnic background greatly contributes to pharmacokinetic dif- ferences as shown in a Spanish population, known to present one of the highest frequencies of these SNP among Caucasians [9]. To our acknowledgment no previous information about CYP2C8 genotype and CYP2C8/CYP2C9 linkage influence on tenoxicam pharmacokinetic has been published. In this context we performed the current study, whose main objective is to quantify the influ- ence of CYP2C9 and CYP2C8 alleles on the variability observed in pharmacokinetics studies with tenoxicam and the possible impli- cation for the adequacy of bioequivalence study designs in Spanish populations. 1043-6618/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2008.09.018