Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists|[ast]|

doi:doi:10.1016/j.clpt.2005.08.015

Clinical Pharmacology & Therapeutics homepage

Clinical Pharmacology & Therapeutics (2005) 78, 619–626; doi: 10.1016/j.clpt.2005.08.015

Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists^*

Melih O. Babaoglu MD^1,2, Banu Bayar MD^1,2, A. Sukru Aynacioglu MD^1,2, Reinhold Kerb MD^1,2, Huseyin Abali MD^1,2, Ismail Celik MD^1,2 and Atila Bozkurt MD, PhD^1,2

¹Departments of Pharmacology and Medical Oncology, Hacettepe University Faculty of Medicine, Ankara
²Pharmacogenetics Laboratory, Epidauros Biotechnology, Bernried.

Correspondence: Melih O. Babaoglu, MD, Department of Pharmacology, Hacettepe University Faculty of Medicine, 06100 Sihhiye, Ankara, Turkey. E-mail: babaoglu@hacettepe.edu.tr

^*This study was supported by grants from the Scientific and Technical Research Council of Turkey (SBAG COST B15-2356) and from the German Ministry for Education and Research (BMBF grant 01 GG9846).

Received 1 April 2005; Accepted 16 August 2005.

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Abstract

Background: Resistance to antiemetic treatment with 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists is still a major problem resulting in patient discomfort and poor compliance to chemotherapy. We hypothesized that clinical resistance to 5-HT₃ antagonists is associated with the single-nucleotide polymorphism (3435C > T) in the gene that codes for the drug efflux transporter adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1).

Methods: Patients with cancer (N = 216) treated with chemotherapeutic regimens composed of highly or moderately emetogenic agents were examined for their antiemetic responses to tropisetron, ondansetron, or granisetron. The efficacy of antiemetic treatment was documented by self-report charts for 5 days after chemotherapy. ABCB1 3435C > T genotype was determined to analyze its association with the antiemetic efficacy of 5-HT₃ antagonists.

Results: Within the first 24 hours of chemotherapy, the complete control rate of nausea and vomiting was higher in subjects with the ABCB1 TT genotype (n = 49) as compared with those with the CC (n = 60) or CT (n = 107) genotype (P = .044). The type of 5-HT₃ antagonists influenced the effect of genotype on antiemetic responses. The complete control rates were 92.9% in TT subjects (n = 14) in comparison to homozygote (47.6%, n = 21, P = .009) or heterozygote (56.1%, n = 41, P = .02) carriers of the 3435 C allele in granisetron-treated patients. However, during the delayed phase of chemotherapy, the complete control rates did not differ across genotypes.

Conclusion: These results suggest that ABCB1 3435C > T polymorphism is associated with antiemetic treatment efficacy in patients with cancer treated with 5-HT₃ antagonists, particularly in granisetron-treated patients, during the short-term phase of chemotherapy.