This study suggests that the cooperative influence of functional polymorphisms in SLCO1B3 and ABCB1 genes may be responsible for the interindividual variability in docetaxel disposition in Asian nasopharyngeal cancer patients.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel.• The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. • Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing. WHAT THIS STUDY ADDS• The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n = 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n = 50).• Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition.• This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMSTo completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n = 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients. METHODSGenomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK. RESULTSA strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P = 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,•)): r 2 = 29% and 22%, respectively]. Patients harbouring the GAG*347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,•) of docetaxel compared with patients harbouring the reference haplotype, GGA*347wt (P = 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the re...

The present exploratory study identified several SNPs in the genes encoding regulatory nuclear receptors which may account for the interpatient variability in docetaxel pharmacokinetics and pharmacodynamics. These findings highlight the important role of regulatory nuclear receptors on the disposition of docetaxel.

Chronomodulated dose-intensified XELOX facilitates delivery of dose-intense treatment in mCRC with a favorable therapeutic index that is promising.

Tamoxifen (TAM) is a prodrug with a complex metabolic pathway involving several metabolic enzymes. Although TAM is mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4/5 enzymes, other CYP enzymes such as CYP1A2, CYP2B6, CYP2C9, and CYP2C19, also catalysed the metabolism of TAM to N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OHT) and endoxifen (END) with 4OHT and END being the active metabolites of TAM. The aim of this study was to investigate the impact of CYP2C19 polymorphisms on the plasma concentrations and metabolic ratios of TAM and its three metabolites, NDM, 4OHT and END. The exons and intron-boundaries of CYP2C19 gene as well as the upstream and downstream regions (about 14 kilobases) were sequenced in 240 Asian healthy subjects (Chinese, Malay, Indians, N=80 each) to identify the polymorphisms present in Asian population. Linkage disequilibrium between identified polymorphisms was examined via Haploview (version 4.0) and tag-SNPs were identified via TAGGER. These tag-SNPs were subsequently genotyped in 164 Asian breast cancer patients using direct sequencing. Plasma levels of TAM and its metabolites were determined at steady state using HPLC with fluorescence detection. Genotypic-phenotypic associations were performed using non-parametric Kruskal-Wallis test and Mann-Whitney U-test. A moderate linkage pattern was observed across the CYP2C19 polymorphisms in the three Asian healthy populations. A total of 13 tag-SNPs and one reported functional SNP were analyzed in Asian breast cancer patients. Patients carrying the AC and CC genotypes of the exonic polymorphism 1251A>C (rs17886522) was associated with 2.3-fold reduction in the median (range) MREND-NDM compared to patients with the reference genotype [AA vs AC+CC: 5.14 (0.92 − 27.81) vs 2.25 (1.26 − 10.72), P = 0.026]. In contrast, median (range) MREND-4-OHT was found to be 1.3-fold higher in patients carrying one or two copies of the −3219T>G variant allele compared to patients carrying the two copies of wild-type allele [TT vs TG + GG: 6.57 (1.99 − 13.18) vs 8.76 (3.78 − 12.80), P = 0.001]. Modest increases in the plasma concentrations of TAM and NDM were associated with 1251A>C (rs17886522). In addition to CYP2D6 polymorphisms, polymorphic variants present in the 5α upstream region of CYP2C19 were found to influence the metabolic ratios of TAM and its metabolites but not the plasma concentrations of the analytes in this exploratory study. The combinative effect of genetic variants in various phase I pharmacogenes on plasma levels of tamoxifen warrants further study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2668. doi:1538-7445.AM2012-2668