title: Effect of the CYP3A5 and ABCB1 genotype on exposure, clinical response and manifestation of toxicities from sunitinib in Asian patients.
abstract: The objective of this study was to determine the effect of the CYP3A5 and ATP binding cassette subfamily B member 1 (ABCB1) single-nucleotide polymorphisms on the disposition of sunitinib and SU12662, on clinical response, and on the manifestation of toxicities in Asian metastatic renal cell carcinoma patients. At week 4 of each treatment cycle, toxicities and plasma steady-state levels were assessed. Clinical response was assessed after two cycles. Genotyping was performed by using the PCR restriction fragment length polymorphism method. The CC genotype for ABCB1 was associated with a higher sunitinib exposure (76.81 vs 56.55 ng ml(-1), P=0.03), higher risk of all-grade rash (RR 3.00, 95% CI 1.17-7.67) and mucositis (RR 1.60, 95% CI 1.10-2.34) and disease progression than compared with the CT/TT genotype. There was a lack of association observed between the CYP3A5 polymorphism and exposure, response and toxicities. The polymorphism of ABCB1 (C3435T) has an important role in the manifestation of toxicities and drug exposure, but not polymorphism of CYP3A5.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.|Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Y L
authors.initials: YL
authors.lastname: Teo
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: H L
authors.initials: HL
authors.lastname: Wee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: X P
authors.initials: XP
authors.lastname: Chue
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: N M
authors.initials: NM
authors.lastname: Chau
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: M-H
authors.initials: MH
authors.lastname: Tan
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: H L
authors.initials: HL
authors.lastname: Wee
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
authors.forename: H K
authors.initials: HK
authors.lastname: Ho
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.|Department of Pharmacy, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Chan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D051544:Cytochrome P-450 CYP3A; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib