Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer

Abstract

AimsThe aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transpor ters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer. MethodsIrinotecan was administered at 100 mg m -2 over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was per formed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes ( CYP3A4 , CYP3A5 , UGT1A1 ) and drug transporters ( ABCB1 , ABCC2 and ABCG2 ) that are involved in irinotecan disposition. ResultsOf the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic-phenotypic associations were apparent only for transpor ter genes. The C max of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of the ABCB1 gene compared with those harbouring at least one variant allele ( P = 0.047). Patients harbouring the wild type ABCG2 CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN-38 compared with patients carrying at least one deletion CTCA allele ( P = 0.019). ConclusionsThe present exploratory study shows that genetic polymorphisms in drug transpor ter genes, particularly in ABCB1 and ABCG2 genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in the ABCG2 and ABCB1 genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations.Q. Zhou et al. 41659 :4 Br J Clin Pharmacol

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…64 However, the latter study also showed an association between the three-SNP haplotype and the C max of SN-38, a product of irinotecan hydrolysis, in the opposite direction to the association described with the single SNP.…”

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…Among other work examining the association between UGT1A1 genotype and cancer, a recent exploratory study examined the role of enzyme and transporter polymorphisms in irinotecan disposition in 29 nasopharyngeal carcinoma patients (Zhou et al, 2005). Of the 11 candidate genes studied, polymorphisms in the drug transporter genes were found to affect irinotecan disposition.…”

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

“…Thus the lack of MDR1/Pgp in humans may be either early lethal (very unlikely) or harmless. In the case of ABCG2, individuals with genes coding for a nonfunctional ABCG2 (a truncated form of the protein) have been found in a low percentage (141,428), with no apparent disease condition. However, it has been suggested that drug hypersensitivity (188,242,251) and even alfalfa hypersensitivity (see Refs.…”