Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 Polymorphisms with the Pharmacokinetics of Paclitaxel

Abstract

Purpose: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). Experimental Design: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m 2 ). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with oneway ANOVA. Results: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium.The population typical value of clearance of unbound paclitaxel was 301L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. Conclusions: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

“…42 To our knowledge, this is the largest prospective study reporting this association. The results, however, are in somewhat contrast to Henningsson et al 43 who found no correlation between clearance and CYP2C8*3, CYP2C8*4 and ABCB1 C3435T in 97 patients (male and female) treated with paclitaxel (80-225 mg m -2 ) and Marsh et al 44 who found no correlation between clearance and CYP2C8*3, CYP2C8*4, ABCB1 C1236T and ABCB1 G2677T in 93 patients with breast cancer treated with 24-h paclitaxel infusion (575-775 mg m -2 ). This discrepancy can be explained by chance or: in case of the study by Henningsson et al, by gender in so far that Joerger et al 45 showed a 20% higher elimination of paclitaxel in males than in females, and in the case of the study by Marsh et al 46 by the nonlinear elimination of paclitaxel reported in the studied population.…”

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

“…34 One recent study in ovarian cancer identified an association between ABCB1 2677G4A/T and response to paclitaxel in 53 Swedish ovarian cancer patients, 35 but this could not be replicated in a larger ovarian cancer study, 36 and was not seen in the breast cancer patients in this study. Although in vitro evidence suggests a role for CYP2C8 and CYP3A4 in paclitaxel metabolism, 4,5 it is possible that other variables such as epigenetic regulation mask these effects in vivo.…”

Cytochrome P450 pharmacogenetics and cancer

“…This question has been dealt with by Nakajima et al (2005), who found a 16-fold interindividual variation in the 6a-hydroxypaclitaxel area under the curve (AUC) among 23 female ovarian cancer patients, but apparently no CYP2C8 variant alleles, due to the small study or low frequency of the alleles in Japanese. Recently, Henningsson et al (2005), using 97 patients, found a 13-fold variation in paclitaxel clearance but no significant influence of the CYP2C8*2, CYP2C8*3 and CYP2C8*4 variant alleles. This issue, however, warrants further investigations.…”