Long-term pharmacokinetic efficacy and safety of low-dose ritonavir as a booster and atazanavir pharmaceutical formulation based on solid dispersion system in rats
Long-term pharmacokinetic efficacy and safety of low-dose ritonavir as a booster and atazanavir pharmaceutical formulation based on solid dispersion system in rats
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DOI：
10.1248/bpb.31.1209
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发表时间：
2008-06-01
影响因子：
2
通讯作者：
Takada, Kanji
中科院分区：
文献类型：
--
作者：
Fukushima, Keizo;Haraya, Kenta;Takada, Kanji
Atazanavir（ATV）与低剂量利托那韦（RTV）合用，通过抑制细胞色素P450（CYP）3A和P-糖蛋白（Pgp），提高ATV的口服生物利用度（BA），但众所周知，在慢性期，RTV对Pgp和CYP 3A的抑制作用变为诱导作用。在这项研究中，我们研究了RTV-加强的ATV在大鼠中的长期有效性和安全性，ATV和RTV的临床相关剂量分别为7 mg/kg和2 mg/kg，并与RTV-加强的ATV和先前报道的基于固体分散系统的ATV药物制剂（ATV-SLS SD+G）进行了直接比较。在药代动力学研究中，大鼠接受RTV增强的ATV或ATV-SLS SD+G 14 d。此外，在每种制剂重复给药14天后，给予大鼠环孢菌素A（CyA），并进行Pgp和CVP 3A的蛋白质印迹分析，以研究对每种ATV制剂的药代动力学相互作用的影响。两种制剂重复给药后，第1天和第14天的ATV药代动力学参数无显著差异;因此，认为两种ATV制剂的长期疗效得以维持。然而，在用RTV增强ATV后，C-max和AUC（0-无穷大），与对照相比，随后的CyA分别显著降低至49%和47%，并且通过蛋白质印迹分析，小肠中的Pgp表达比对照高约2倍，而在用ATV药物制剂处理后，未观察到CyA的显著变化，也未观察到肠Pgp和肝CVP 3A的表达的显著变化。因此，认为在用RTV加强的ATV处理后，CyA的BA将通过RTV在慢性期的诱导作用而降低，如上所述。本研究的结果表明，长期使用低剂量RTV作为助推剂具有很大的潜力，损害药物相互作用;因此，建议通过药物方法改善蛋白酶抑制剂的BA，而不与RTV发生药代动力学相互作用。
Atazanavir (ATV) is clinically coadministered with low-dose ritonavir (RTV), which boosts the oral bioavailability (BA) of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway, however, it is well known that in the chronic phase, the inhibition effect of RTV on Pgp and CYP3A becomes an induction effect. In this study, we investigated the long-term efficacy and safety of RTV-boosted ATV in rats with a clinical relevant dosage of ATV and RTV, 7 mg/kg and 2 mg/kg, respectively, and drew a direct comparison with RTV-boosted ATV and the previously reported ATV pharmaceutical formulation based on a solid dispersion system (ATV-SLS SD+G). Rats received RTV-boosted ATV or ATV-SLS SD+G for 14 d in the pharmacokinetic study. In addition, after 14-d repeated administration of each formulation, cyclosporine A (CyA) was administered to rats and Western blot analysis of Pgp and CVP3A was performed to investigate the impact on pharmacokinetic interaction of each ATV formulation. After repeated administration of both formulations, there was no significant difference between ATV pharmacokinetic parameters on day 1 and 14; therefore, it was considered that the long-term efficacy of both ATV formulations was maintained. However, after treatment with RTV boosted ATV, the C-max and AUC(0-infinity) of the following CyA significantly decreased to 49% and 47%, in comparison to the control, respectively, and the Pgp expression in the small intestine by Western blot analysis was approximately 2-fold higher than the control, whereas after treatment with ATV pharmaceutical formulation, neither significant alteration of CyA nor notable change in the expression of intestinal Pgp and hepatic CVP3A was observed. Therefore, it was considered that the BA of CyA after treatment with RTV-boosted ATV would decrease by the induction effect of RTV in chronic phase as described above. The results of this study revealed that the chronic use of low-dose RTV as a booster has great potential to compromise drug-drug interactions; therefore, it is recommended that the BA of protease inhibitors be improved by a pharmaceutical approach without pharmacokinetic interaction by RTV.