Abstract
Abstract 2063 Background: CPT-11 has an extremely complex metabolic pathway and its disposition is greatly influenced by several enzymes (carboxylesterases, CYP3A4/5 and UGT1A1) and ABC transporters (ABCB1, ABCC2 and ABCG2). The objective of this study was to correlate SNPs in drug metabolising enzymes and ABC transporters proteins to the disposition kinetics of CPT-11 and its metabolites, SN-38 and SN-38G in Chinese nasopharyngeal carcinoma (NPC) patients (N=30). CPT-11 was administered at a fixed dose of 100 mg/m(2) over 90 minutes. Pharmacokinetic and pharmacogenetic analysis were done on day 1 of cycle 1. All patients were genotyped for the following SNPs: CYP3A4*1B, *4, *5 and *6; CYP3A5*3 and *6; UGT1A1 5'UTR [T-3263G] and UGT1A1*28; ABCB1 [C1236T, G2677T/A, C3435T]; ABCC2 [5'UTR: C-24T; exon 4 C-49T]; and ABCG2 [-19572-19569 CTCA deletion, G34A, C376T, C421A]. The estimated variant genotype frequencies were as follows: CYP3A5*3/*3 (11%), UGT1A1 [T-3263G (36%) and *28 (7%)], ABCB1 (25-39%), ABCC2 C-24T (4%) and C-49T (7%), ABCG2 [CTCA del (4%), G34A (4%), C421A (11%)]. All patients were wild-type for CYP3A4 SNPs. The clearance and relative extent of conversion of CPT-11 was 30.5±2.6 L/hr/m(2) and 0.9±10.5%, respectively. A trend towards decreased CPT-11 clearance was noted for ABCB1 C3435T SNP with (CT+TT) carriers having lower clearance (p=0.072) and increased AUC0-∞(p=0.072) and Cmax (p=0.046) compared with CC carriers. A significant association was found between SN-38G Cmax and ABCB1C1236T polymorphism (p=0.037). A significant association was also found between ABCG2 G34A SNP and CPT-11 Cmax, with GG patients showing lower exposures compared with (GA+AA) patients (p=0.045). Although CPT-11 PK seems to be associated with ABC transporter SNPs, further validation of the results in a larger patient sample is required. No significant financial relationships to disclose.
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