Mugundu Ganesh M, Hariparsad Niresh, Desai Pankaj B
Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0004, USA.
Drug Metab Lett. 2010 Jan;4(1):45-50. doi: 10.2174/187231210790980453.
Currently used combinations of anti-HIV drugs, known as Highly Active Antiretroviral Therapy (HAART), have considerably reduced the mortality in patients with AIDS. However, HAART medications such as efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) often cause adverse drug-drug interactions (DDIs) that result from changes in the expression and activity of drug metabolizing enzymes. Since EFV is most commonly used with ATV and RTV, the known CYP inhibitors, we evaluated the effects of combinations of these agents on the CYP3A4 induction by EFV. We determined the induction of CYP3A4 by EFV, RTV, ATV, EFV+RTV, EFV+ATV, EFV+RTV+ATV and rifampicin (RIF) employing primary human hepatocytes from 3 donors. Also, concentration dependent activation of human Pregnane X-receptor (hPXR) which is key transcriptional regulator of CYP3A4 by EFV, RIF and RTV was estimated in transiently transfected LS180 cells. CYP3A4 activity (testosterone-6beta-hydroxylation) was induced by EFV (3 fold) and RIF (4 fold), but was significantly suppressed in the presence of RTV and ATV. All treatments significantly induced the CYP3A4 transcripts (3-25 fold) as quantitated by RT-PCR. hPXR activation data in LS180 cells were consistent with the induction of transcripts and the estimated EC(50) values were 0.87 microM, 0.44 microM and 3.7 microM for RIF, RTV and EFV, respectively. However, in primary hepatocytes the net effect was suppression of EFV mediated CYP3A4 induction by RTV and ATV. This observation corresponds to the clinical observations of attenuated CYP3A4 induction by EFV induction in the presence of RTV and other protease inhibitors (PIs). Our results underscore the limitation of transcriptional activation assays in predicting the net outcome for compounds that exhibit complex interactions resulting from induction and inhibition of CYP enzymes.
目前使用的抗艾滋病毒药物组合，即高效抗逆转录病毒疗法（HAART），已显著降低了艾滋病患者的死亡率。然而，诸如依非韦伦（EFV）、阿扎那韦（ATV）和利托那韦（RTV）等HAART药物常常会引发不良药物相互作用（DDIs），这是由药物代谢酶的表达和活性变化所导致的。由于EFV最常与已知的CYP抑制剂ATV和RTV联用，我们评估了这些药物组合对EFV诱导CYP3A4的影响。我们使用来自3名供体的原代人肝细胞，测定了EFV、RTV、ATV、EFV+RTV、EFV+ATV、EFV+RTV+ATV和利福平（RIF）对CYP3A4的诱导作用。此外，在瞬时转染的LS180细胞中，评估了EFV、RIF和RTV对人孕烷X受体（hPXR）的浓度依赖性激活，hPXR是CYP3A4的关键转录调节因子。EFV（3倍）和RIF（4倍）可诱导CYP3A4活性（睾酮-6β-羟化），但在RTV和ATV存在的情况下，其活性显著受到抑制。通过逆转录-聚合酶链反应（RT-PCR）定量分析，所有处理均显著诱导了CYP3A4转录本（3-25倍）。LS180细胞中的hPXR激活数据与转录本的诱导情况一致，RIF、RTV和EFV的估计半数有效浓度（EC50）值分别为0.87微摩尔、0.44微摩尔和3.7微摩尔。然而，在原代肝细胞中，净效应是RTV和ATV抑制了EFV介导的CYP3A4诱导。这一观察结果与临床观察结果相符，即在RTV和其他蛋白酶抑制剂（PIs）存在的情况下，EFV诱导的CYP3A4诱导作用减弱。我们的结果强调了转录激活试验在预测因CYP酶诱导和抑制而表现出复杂相互作用的化合物的净结果方面的局限性。
