Impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 genetic polymorphisms on vincristine-induced neurotoxicity
| Autor: | Véronique Bourgarel-Rey, Nicolas Simon, Bruno Lacarelle, Caroline Solas, Romain Guilhaumou, Angélique Rome, Sylvie Quaranta, Nicolas André |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research Vincristine ATP Binding Cassette Transporter Subfamily B Adolescent Genotype Pharmacology Toxicology Pharmacokinetics Neoplasms medicine Cytochrome P-450 CYP3A Humans Pharmacology (medical) ATP Binding Cassette Transporter Subfamily B Member 1 Child Body surface area Polymorphism Genetic CYP3A4 business.industry Neurotoxicity medicine.disease Antineoplastic Agents Phytogenic Oncology Child Preschool Toxicity Female Neurotoxicity Syndromes business Pharmacogenetics Intracellular medicine.drug |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 68:1633-1638 |
| ISSN: | 1432-0843 0344-5704 |
| DOI: | 10.1007/s00280-011-1745-2 |
| Popis: | The aim of this study was to investigate the impact of plasma and intracellular exposure and CYP3A4, CYP3A5, and ABCB1 polymorphisms on vincristine neurotoxicity. We subsequently assessed the impact of ABCB1 polymorphisms on intracellular vincristine accumulation.Children treated for solid tumors were enrolled in the study (n = 26) and received 1.5 mg/m² of vincristine per course. Individual pharmacokinetic parameters and CYP3A4, CYP3A5, and ABCB1 genotypes were available from a previous analysis. A global toxicity score (pain, peripheral neurotoxicity, and gastrointestinal toxicity) was collected at each course. Vincristine in plasma and PBMCs were quantified by LC-MS/MS.Vincristine plasma and intracellular concentrations ranged from 0.40 to 89.6 ng/ml and from 0.00225 to 1.85 ng/10(6) cells over a 24-h interval, respectively. The global toxicity score ranged from 0 to 6 and was not correlated with individual pharmacokinetics parameters. Neurotoxicity events (global score ≥ 3) were observed in 8 patients but the incidence was not influenced by the different studied polymorphisms. The global toxicity score was correlated with age, body surface area, and dose in mg. A trend to higher intracellular/plasma ratio of vincristine was found for patients with heterozygous diplotype (CGC-TTT) of ABCB1.None of the different genetic covariates nor plasma and intracellular exposure was predictive of the observed neurotoxicity in our pediatric population. Nevertheless, the heterozygote diplotype of ABCB1 appears to influence the intracellular accumulation of vincristine. Owing to the small sample size, further evaluations are needed in a larger patient cohort. |
| Databáze: | OpenAIRE |
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