The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment
| Autor: | Renan Canibal Pires, Mara H. Hutz, Maria Elvira Wagner Ferreira, Luiz Carlos Van der Sand, Fabiano Roldao Silveira, Cézar Roberto Van der Sand, Marilu Fiegenbaum |
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| Rok vydání: | 2005 |
| Předmět: |
Adult
Male myalgia Simvastatin medicine.medical_specialty Pharmacology Biology Polymorphism Single Nucleotide Gastroenterology chemistry.chemical_compound Cytochrome P-450 Enzyme System Internal medicine medicine Cytochrome P-450 CYP3A Humans Pharmacology (medical) Prospective Studies CYP3A5 Prospective cohort study Alleles Aged Aged 80 and over Reverse Transcriptase Polymerase Chain Reaction Cholesterol Cholesterol HDL Genetic Variation Cholesterol LDL DNA Middle Aged Lipids Hydroxymethylglutaryl-CoA reductase Confidence interval Haplotypes Tolerability chemistry ATP-Binding Cassette Transporters Female Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.symptom ATP Binding Cassette Transporter 1 medicine.drug |
| Zdroj: | Clinical Pharmacology & Therapeutics. 78:551-558 |
| ISSN: | 0009-9236 |
| DOI: | 10.1016/j.clpt.2005.08.003 |
| Popis: | Our objective was to investigate the interactions between common polymorphisms in ABCB1, CYP3A4, and CYP3A5 genes and the lipid-lowering efficacy and safety of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin.One hundred sixteen hypercholesterolemic patients were prospectively screened by physical examination, medical history, and clinical laboratory evaluation and were included in this study. Subjects entering the study were treated with 20 mg/d simvastatin. Plasma lipid and lipoprotein levels were measured before treatment, after 2 months of treatment, and after 6 months of treatment. Ninety-nine patients completed the 6-month follow-up and were included in the association analysis for treatment efficacy. Seventeen subjects who had adverse drug reactions (ADRs) to simvastatin (ADR group) could not complete the 6-month follow-up and were included in the association analyses for safety. Myalgia was observed in 15 of 17 subjects and was the only ADR included in the association analyses, but other common ADRs were also observed. Myalgia was defined as proximal or diffuse muscle pain, tenderness, or weakness, or both pain and weakness, with normal or slightly increased serum creatine phosphokinase levels. ABCB1 (1236CT, 2677GA/T, and 3435CT), CYP3A4 (-392AG), and CYP3A5 (6986AG) allele variants were determined by polymerase chain reaction and restriction mapping.After adjustment for covariates, carriers of the ABCB1 1236T variant allele had a greater reduction in total cholesterol and low-density lipoprotein cholesterol with simvastatin treatment, as compared with homozygotes with the wild-type allele (-29.0% [95% confidence interval (CI), -25.9 to -32.5] versus -24.2% [95% CI, -19.0 to -29.3] [P = .042] and -39.6% [95% CI, -35.8 to -44.0] versus -33.8% [95% CI, -27.4 to -40.2] [P = .042], respectively). Similar results were observed for the 2677GA/T polymorphism and haplotype data. The 1236T, 2677non-G, and 3435T alleles were less frequent in ADR cases than in the non-ADR group (P.05 for all single-nucleotide polymorphisms). Haplotype analyses also demonstrated a reduction of the T-non-G-T haplotype frequency (20%) in patients in whom myalgia developed during simvastatin treatment, as compared with the non-ADR group (41.4%) (P = .03). No significant associations were observed between the CYP3A4 -392AG and CYP3A5*3 allele variants and the efficacy or tolerability of simvastatin.Our data suggest an association of ABCB1 gene polymorphisms and the efficacy and safety of simvastatin. |
| Databáze: | OpenAIRE |
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