Effect of CYP3A5*3 on carbamazepine pharmacokinetics in Japanese patients with epilepsy

Abstract

Our data obtained from subjects whose CYP3A activities were also induced by carbamazepine itself coincided with their results. In these studies of Asian subjects the induced CYP3A activities in the CYP3A*3/*3 subjects lacking CYP3A5 were not inferior to those in the rest. Large racial differences in the frequencies of the CYP3A5 variants and haplotypes have been reported. 1,4 The mechanism(s) regulating the hepatic CYP3A expression may also be different among races because the level of CYP3A4 messenger ribonucleic acid did not correlate with the level of CYP3A5 messenger ribonucleic acid in livers in Japanese subjects in contrast to the coregulatory expression of CYP3A4 and CYP3A5 in livers in white subjects. 4,5 Mouly et al 2 questioned whether the effect of CYP3A5 genotype observed in healthy volunteers might be evident in treated patients with human immunodeficiency virus, and this remains unanswered. The clinical impact of the CYP3A5*3 genotypes should thus be clarified further with regard to the influences of substrates, multigene haplotypes, races, and environmental factors. 1,2

Effect of CYP3A5 Genotypes on the Pharmacokinetics of Carbamazepine when used as Monotherapy or Co-Administered with Phenytoin, Phenobarbital or Valproic Acid in Thai Patients

“…This result conflicted with the result from the study by Park et al of 35 Korean epileptic patients, who reported that the CBZ clearance in patients with homozygous CYP3A5*3/*3 was 29% lower than that observed in patients with at least one CYP3A5*1 allele [16]. Seo et al [15] recruited patients who used CBZ as either monotherapy or concurrently with the potent inducer of CYP3A, i.e. PHT and PB, into their study which may confound the effect of CYP3A5 genotypes on CBZ pharmacokinetics.…”

“…Because CYP3A5 may represent up to 50% of the total CYP3A protein in individuals polymorphically expressing CYP3A5, it may have a major role in the variation of CYP3A-mediated drug metabolism [22][23]. A previous study by Seo et al of 144 Japanese epileptic patients reported that patients with CYP3A5*3/*3 exhibited CBZ clearance 8% higher than patients not carrying CYP3A5*3/*3 [15]. This result conflicted with the result from the study by Park et al of 35 Korean epileptic patients, who reported that the CBZ clearance in patients with homozygous CYP3A5*3/*3 was 29% lower than that observed in patients with at least one CYP3A5*1 allele [16].…”

“…We excluded pregnant women, patients with hepatic disease or renal disease. Additionally, patients who were concurrently using drugs which may interact with CBZ pharmacokinetics (except PHT, PB and VPA) were excluded, namely verapamil, diltiazem, haloperidol, theophylline, ticlopidine, cimetidine, omeprazole, trazodone, fluoxetine, risperidone, clarithromycin, erythromycin, rifampicin, isoniazid, isotretrinion, gemfibrozil and metronidazole [14][15][16]. Grapefruit consumers, if any, were excluded.…”

“…Among several factors that have been reported as influencing the elimination of CBZ, age, body weight, surface area, dose of CBZ, and comedication with PHT, PB, or VPA [8,9,[12][13][14], CYP3A5 polymorphism have more recently received greater focus. Seo et al reported CBZ clearance in patients with CYP3A5*3/*3 to be 8% significantly higher than that in patient with CYP3A5*1/*1 or CYP3A5*1/*3 [15].…”

CYP3A5 Polymorphism In Serbian Paediatric Epileptic Patients On Carbamazepine Treatment

“…However, due to conflicting reports, the evidence of association between carbamazepine treatment outcomes and CYP3A5 functional variations remains inconclusive. As an example, although CYP3A5 genotype affected serum concentration of carbamazepine in Koreans (15), Chinese (16), and Japanese (17), as well as drug half-life in African-Americans (18), no influence of carbamazepine pharmacokinetics parameters were observed in Caucasian epileptic patients (18). The apparent underlying cause of this discrepancy might be interethnic variability, which represents a multidimensional determinant that comprises both genetic heritage and environment (19,20).…”