SLCO1B1 多态性对 HIV 感染男性患者洛匹那韦和利托那韦血药浓度的影响。
The impact of SLCO1B1 polymorphisms on the plasma concentration of lopinavir and ritonavir in HIV-infected men.
机构信息
Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
出版信息
Br J Clin Pharmacol. 2010 Jan;69(1):95-8. doi: 10.1111/j.1365-2125.2009.03551.x.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
- There is large interindividual variability in the pharmacokinetics of protease inhibitors (PIs) among human immunodeficiency virus (HIV)-infected individuals under highly active antiretroviral therapy. * Protease inhibitor have been recently reported to be substrates of the SLCO1B1/OATP1 drug transporter. * A single nucleotide polymorphism (SNP) in the SLCO1B1 gene (521T-->C) was associated with plasma levels of lopinavir in HIV-infected individuals.
WHAT THIS STUDY ADDS
- Data on the impact of three SLCO1B1 SNPs (521T-->C, 388A-->G, 463C-->A) on the trough plasma concentration of lopinavir and ritonavir in a cohort of 99 adult HIV-infected Brazilian men under stable highly active antiretroviral therapy. * Evidence that carriers of the 521C allele display significantly higher lopinavir, but not ritonavir plasma concentrations relative to the wild-type TT genotype. * No effect of either 388A-->G or 463C-->A SNPs on lopinavir or ritonavir plasma concentrations. * Further studies are required to confirm the clinical significance of the association between the SLCO1B1521T-->C polymorphism and lopinavir pharmacokinetics.
AIMS
To investigate possible associations between three SLCO1B1 single nucleotide polymorphisms (388A-->G, 463C-->A, 521T-->C) and lopinavir/ritonavir plasma concentrations.
METHODS
The study included 99 human immunodeficiency virus-infected men on stable highly active antiretroviral therapy containing lopinavir/ritonavir. Trough concentrations of lopinavir and ritonavir in plasma were quantified using liquid chromatography-tandem mass spectrometry. Genotyping of SLCO1B1388A-->G, 463C-->A and 521T-->C polymorphisms was performed by allelic discrimination using real-time polymerase chain reaction.
RESULTS
The trough concentration of lopinavir in plasma is significantly associated with SLCO1B1521T-->C genotypes (P= 0.03). There is a significant trend for increasing concentrations of lopinavir from TT to TC to CC genotypes (P= 0.02). Carriers of the 521C allele display significantly higher lopinavir plasma concentrations relative to the wild-type TT genotype (P= 0.03).
CONCLUSIONS
Reduced uptake of lopinavir by hepatocytes in carriers of the 521C allele may account for these results, but further studies to confirm the clinical importance of SLCO1B1 polymorphisms in lopinavir pharmacokinetics are warranted.
已知信息：
在接受高效抗逆转录病毒治疗的人类免疫缺陷病毒（HIV）感染者中，蛋白酶抑制剂（PI）的药代动力学存在很大的个体间差异。
最近有报道称，蛋白酶抑制剂是 SLCO1B1/OATP1 药物转运体的底物。
SLCO1B1 基因中的单核苷酸多态性（SNP）（521T-->C）与 HIV 感染者中洛匹那韦的血浆水平有关。
本研究新增信息：
在 99 名接受稳定高效抗逆转录病毒治疗的成年巴西 HIV 感染男性中，关于三个 SLCO1B1 SNPs（521T-->C、388A-->G、463C-->A）对洛匹那韦和利托那韦的谷浓度的影响的数据。
证据表明，521C 等位基因的携带者显示出明显更高的洛匹那韦，但与野生型 TT 基因型相比，利托那韦的血浆浓度没有差异。
388A-->G 或 463C-->A SNP 对洛匹那韦或利托那韦的血浆浓度均无影响。
需要进一步研究来确认 SLCO1B1521T-->C 多态性与洛匹那韦药代动力学之间的关联的临床意义。
目的：研究三个 SLCO1B1 单核苷酸多态性（388A-->G、463C-->A、521T-->C）与洛匹那韦/利托那韦血浆浓度之间可能存在的关联。
方法：该研究包括 99 名接受稳定高效抗逆转录病毒治疗且含有洛匹那韦/利托那韦的 HIV 感染男性。使用液相色谱-串联质谱法定量测定洛匹那韦和利托那韦在血浆中的谷浓度。使用实时聚合酶链反应进行等位基因鉴别，对 SLCO1B1388A-->G、463C-->A 和 521T-->C 多态性进行基因分型。
结果：洛匹那韦在血浆中的浓度与 SLCO1B1521T-->C 基因型显著相关（P=0.03）。从 TT 到 TC 再到 CC 基因型，洛匹那韦的浓度呈显著升高趋势（P=0.02）。521C 等位基因的携带者与野生型 TT 基因型相比，洛匹那韦的血浆浓度明显更高（P=0.03）。
结论：携带 521C 等位基因的肝细胞对洛匹那韦的摄取减少可能导致了这些结果，但需要进一步研究来证实 SLCO1B1 多态性在洛匹那韦药代动力学中的临床重要性。
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