期刊
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
卷 66, 期 9, 页码 2092-2098出版社
OXFORD UNIV PRESS
DOI: 10.1093/jac/dkr272
关键词
pharmacogenetics; pharmacokinetics; metabolism; drug disposition
资金
- Clinical Trial Centre Cologne
- UK Medical Research Council [G0800247]
- German Competence Network for HIV/AIDS
- BMBF (Bundesministerium fur Bildung und Forschung) [01 KI 0771]
- Federal Ministry of Education and Research [BMBF 01 KI 0501]
- Else Kroener Foundation
- Boehringer Ingelheim
- GlaxoSmithKline
- Abbott Laboratories
- Pfizer
- AstraZeneca
- Tibotec
- Merck
- Roche Pharmaceuticals
- MRC [G0800247] Funding Source: UKRI
- Medical Research Council [G0800247] Funding Source: researchfish
Objectives: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. Methods: Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G -> T, rs3745274), CAR (540C -> T, rs2307424) and PXR (44477T -> C, rs1523130; 63396C -> T, rs2472677; and 69789A -> G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. Results: Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [ odds ratio (OR)=0.27; P=0.0001], CYP2B6 516TT (OR=2.81; P=0.006), CAR rs2307424 CC (OR=1.92; P=0.007) and smoking status (OR=0.45; P=0.002) were associated with discontinuation within 3 months. Conclusions: These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.
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