Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS

作者：Liptrott Neill J; Pushpakom Sudeep; Wyen Christoph; Faetkenheuer Gerd; Hoffmann Christian; Mauss Stefan; Knechten Heribert; Brockmeyer Norbert H; Hopper Borge Elizabeth; Siccardi Marco; Back David J; Khoo Saye H; Pirmohamed Munir; Owen Andrew^*

来源：Pharmacogenetics and Genomics, 2012, 22(1): 10-19.

DOI：10.1097/FPC.0b013e32834dd82e

• ABCC10
• CD4+lymphocyte
• drug efflux transporter
• HIV
• monocyte-derived macrophage
• nevirapine
• single nucleotide polymorphism

Background Nevirapine exhibits marked interpatient variability in pharmacokinetics. CYP2B6 activity and demographic factors are important, but there are a few data on drug transporters for nevirapine. ABCC10 (MRP7) is an efflux transporter highly expressed in liver, intestine, and peripheral blood cells. We investigated whether nevirapine is a substrate for ABCC10 and whether genetic variants contribute to variability in nevirapine plasma concentrations. %26lt;br%26gt;Methods Accumulation of nevirapine was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4+ cells, and monocyte-derived macrophages from healthy volunteers (n = 8). ABCC10 small interfering RNA studies were also conducted. DNA samples with paired plasma drug concentrations were available from 163 HIV-infected patients receiving nevirapine-containing regimens. Sequenom was used to screen 14 single nucleotide polymorphisms in ABCC10. Linear regression models were used to identify factors independently associated with nevirapine plasma concentration. %26lt;br%26gt;Results Nevirapine accumulation was 37% lower in HEK293-ABCC10 cells compared with parental HEK293 cells (P=0.02), and this was reversed by cepharanthine (an ABCC10 inhibitor). After small interfering RNA knockdown of ABCC10, there was an increase in accumulation of nevirapine in CD4 cells (32%; P=0.03) and monocyte-derived macrophages (38%; P=0.04). Marked differences in the haplotype structure of ABCC10 was observed between White and Black patients in the cohort. In Whites, an exonic single nucleotide polymorphism (rs2125739) was significantly associated with nevirapine plasma concentration (P=0.02). Multivariate regression analysis identified carriage of a composite genotype of ABCC10 rs2125739 and CYP2B6 516G%26gt;T (P=0.001), time post dose (P=0.01) and BMI (P=0.07) to be independently associated with nevirapine plasma concentrations. %26lt;br%26gt;Conclusion Nevirapine is a substrate for ABCC10 and genetic variants influence its plasma concentrations. ABCC10 in lymphocytes and macrophages may also contribute to variability in intracellular permeation of nevirapine. Further studies are required to determine the clinical implications of these findings.

• 出版日期2012-1