The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients

Autor: Balram Chowbay, Onkar Singh, Eng Huat Tan, Wan-Teck Lim, Xiangai Chen, Rathi Devi Ramasamy, Tejal Kulkarni, Edmund J.D. Lee, Sin Chi Chew
Rok vydání: 2011
Předmět:
Male
Cancer Research
medicine.medical_specialty
Pathology
ATP Binding Cassette Transporter
Subfamily B
Antineoplastic Agents
Single-nucleotide polymorphism
Docetaxel
Organic Anion Transporters
Sodium-Independent
Biology
Toxicology
Polymorphism
Single Nucleotide
Gastroenterology
Solute Carrier Organic Anion Transporter Family Member 1B3
Asian People
Pharmacokinetics
Polymorphism (computer science)
Internal medicine
Genotype
medicine
ATP Binding Cassette Transporter
Subfamily G
Member 2
Cytochrome P-450 CYP3A
Humans
Pharmacology (medical)
ATP Binding Cassette Transporter
Subfamily B
Member 1
CYP3A5
Pharmacology
Nasopharyngeal Neoplasms
medicine.disease
Multidrug Resistance-Associated Protein 2
Neoplasm Proteins
Oncology
Nasopharyngeal carcinoma
ATP-Binding Cassette Transporters
Female
Taxoids
Multidrug Resistance-Associated Proteins
Pharmacogenetics
medicine.drug
Zdroj: Cancer Chemotherapy and Pharmacology. 67:1471-1478
ISSN: 1432-0843
0344-5704
DOI: 10.1007/s00280-011-1625-9
Popis: This exploratory study aimed to explain the interindividual variabilities of docetaxel pharmacokinetics and pharmacodynamics in Asian nasopharyngeal carcinoma patients (n = 54) through the genotyping of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 genes. Docetaxel was administered over 1 h on days 1, 8, and 15 every 28 days at 30 mg/m2/dose. Genomic DNA was isolated from peripheral blood and genotyped for the selected polymorphisms in the candidate genes. Docetaxel pharmacokinetic parameters were estimated by non-compartmental modelling. Patients homozygous for the variant allele (GG) of SLCO1B3 rs11045585 (IVS12-5676A > G) had significantly higher area under the plasma concentration–time curve of docetaxel (P = 0.026) and lower clearance (P = 0.036) compared to patients with AA/AG genotypes. Patients harbouring the heterozygous genotype (GA + GT + TA) for ABCB1 rs2032582 (2677G > T/A) had the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with GG/TT genotypes (P = 0.006). Similar trend was observed for ABCB1 rs1045642 (3435C > T) with heterozygotes (CT) having the highest percentage decrease in nadir haemoglobin from cycle 1 baseline compared to those with CC/TT genotypes (P = 0.066). This study suggests that the cooperative influence of functional polymorphisms in SLCO1B3 and ABCB1 genes may be responsible for the interindividual variability in docetaxel disposition in Asian nasopharyngeal cancer patients.
Databáze: OpenAIRE
Externí odkaz: