ABCMdb

ABCB2 p.Gly34Ala

Predicted by SNAP2:	A: N (87%), C: N (72%), D: N (72%), E: N (72%), F: N (57%), H: N (78%), I: N (61%), K: N (82%), L: N (61%), M: N (72%), N: N (87%), P: N (72%), Q: N (82%), R: N (82%), S: N (93%), T: N (82%), V: N (72%), W: D (71%), Y: N (66%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Pharmacogenetic profiling across the irinotecan pa... Br J Clin Pharmacol. 2005 Apr;59(4):415-24. Zhou Q, Sparreboom A, Tan EH, Cheung YB, Lee A, Poon D, Lee EJ, Chowbay B
Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer.
Br J Clin Pharmacol. 2005 Apr;59(4):415-24., [PMID:15801936]

Abstract [show]
AIMS: The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer. METHODS: Irinotecan was administered at 100 mg m(-2) over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed 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. RESULTS: Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic-phenotypic associations were apparent only for transporter 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). CONCLUSIONS: The present exploratory study shows that genetic polymorphisms in drug transporter 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.

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113 Of the nine SNPs analyzed for the ABCG2 gene, variant genotypes Figure 2 Genotype-phenotype associations 1800 1500 1200 900 600 300 0 C max (mg/L) CC CT + TT ABCB1 C3435T Genotype P = 0.047 CPT-11 1200 900 600 300 0 C max (mg/L) CC-GG-CC CT-GT-CT TT-TT-TT ABCB1 Haplotype P = 0.055 SN-38G 1500 1200 900 600 300 0 C max (ng/ml) GG GA + AA ABCB2 G34A Genotype P = 0.056 CPT-11 400 300 200 100 0 AUC 0Æ• (ng*h/ml) CTCA H + delCTCA ABCG2-19572-19569 CTCAdel Genotype P = 0.068 SN-38 0.1 0.12 0.08 0.06 0.02 0.04 0 REC CTCA H + delCTCA ABCG2-19572-19569 CTCAdel Genotype P = 0.019 SN-38G A B C E D were only found for the -19572-19569delCTCA, G34A and C421A SNPs. Login to comment
115 Patients who were wild type for the G34A SNP at exon 2 showed a trend towards lower systemic exposures to irinotecan (i.e. Cmax) compared with patients with one or two variant alleles (Figure 2C, P = 0.056). Login to comment