Effect of the Fluoroquinolone Antibacterial Agent DX-619 on the Apparent Formation and Renal Clearances of 6β-Hydroxycortisol, an Endogenous Probe for CYP3A4 Inhibition, in Healthy Subjects
Effect of the Fluoroquinolone Antibacterial Agent DX-619 on the Apparent Formation and Renal Clearances of 6β-Hydroxycortisol, an Endogenous Probe for CYP3A4 Inhibition, in Healthy Subjects
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DOI：
10.1007/s11095-012-0890-6
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发表时间：
2013-02-01
影响因子：
3.7
通讯作者：
Sugiyama, Yuichi
中科院分区：
文献类型：
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作者：
Imamura, Yuichiro;Murayama, Nobuyuki;Sugiyama, Yuichi
目的 在健康受试者中检查氟喹诺酮 DX-619 对 CYP3A4 和 6 β-羟基皮质醇（肝 CYP3A4 活性的内源性探针）尿排泄的影响。在人肝微粒体中检查 DX-619 对 CYP3A4 的影响。在安慰剂和 DX-619 治疗的受试者中测定了 6 β-羟基皮质醇（分别为 CL6 β-OHF 和 CLrenal,6 β-OHF）的表观形成和肾脏清除率。在表达 OAT1、OAT3、OCT2、MATE1 和 MATE2-K 的 HEK293 细胞中测定了 6 β-羟基皮质醇的摄取。DX-619 是一种基于机制的 CYP3A4 抑制剂，K-I 和 k(inact) 分别为 67.9 +/- 7.3 mu mol/l 和 0.0730 +/- 0.0033 min(-1)。药代动力学模拟表明 DX-619 抑制 CYP3A4 的体内相关性。与安慰剂相比，DX-619治疗组第15天时CL6 beta-OHF和CLrenal,6 beta-OHF分别降低72%和70%（P < 0.05）。 6 β-羟基皮质醇是 OAT3 (K-m = 183 +/- 25 mu mol/l)、OCT2、MATE1 和 MATE2-K 的底物。 DX-619 的最大未结合浓度 (9.1 +/- 0.4 mu mol/l) 高于 DX-619 对 MATE1 的 K-i (4.32 +/- 0.79 mu mol/l)。DX-619 对肝脏 CYP3A4 介导的形成产生中度抑制，并显着抑制 MATE 介导的 6 β-羟基皮质醇流入尿液。在应用 CL6 beta-OHF 作为肝脏 CYP3A4 活性指标而不评估 CLrenal,6 beta-OHF 时需要谨慎。
To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6 beta-hydroxycortisol, an endogenous probe of hepatic CYP3A4 activity, in healthy subjects.The effect of DX-619 on CYP3A4 was examined in human liver microsomes. The apparent formation and renal clearance of 6 beta-hydroxycortisol (CL6 beta-OHF and CLrenal,6 beta-OHF, respectively) were determined in placebo- and DX-619-treated subjects. 6 beta-hydroxycortisol uptake was determined in HEK293 cells expressing OAT1, OAT3, OCT2, MATE1, and MATE2-K.DX-619 was a mechanism-based inhibitor of CYP3A4, with K-I and k(inact) of 67.9 +/- 7.3 mu mol/l and 0.0730 +/- 0.0033 min(-1), respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL6 beta-OHF and CLrenal,6 beta-OHF were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P < 0.05). 6 beta-hydroxycortisol was a substrate of OAT3 (K-m = 183 +/- 25 mu mol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1 +/- 0.4 mu mol/l) was above K-i of DX-619 for MATE1 (4.32 +/- 0.79 mu mol/l).DX-619 caused a moderate inhibition of hepatic CYP3A4-mediated formation and significant inhibition of MATE-mediated efflux of 6 beta-hydroxycortisol into urine. Caution is needed in applying CL6 beta-OHF as an index of hepatic CYP3A4 activity without evaluating CLrenal,6 beta-OHF.