In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: Characterizing the importance of transporter-enzyme interplay
In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: Characterizing the importance of transporter-enzyme interplay
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DOI：
10.1124/dmd.106.009258
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发表时间：
2006-08-01
影响因子：
3.9
通讯作者：
Benet, Leslie Z.
中科院分区：
文献类型：
--
作者：
Lam, Justine L.;Okochi, Hideaki;Benet, Leslie Z.
通过比较大鼠肝微粒体、新鲜分离的肝细胞和体内研究的结果，研究了肝摄取和外排转运蛋白对红霉素（ERY）处置和代谢的影响。在新鲜分离的大鼠肝细胞中进行的摄取研究表明，ERY及其代谢产物（N-去甲基-ERY）是Oatp 1a 4和Oatp 1b 2的底物。而利福平和GG 918 [GF 120918：N-{4-[ 2-（1，2，3，4-四氢-6，7-二甲氧基-2-异喹啉基）-乙基]-苯基}-9，10-二氢-5-甲氧基9-氧代-4-吖啶甲酰胺]对微粒体中的代谢影响极小，利福平（2.5 μ M）和GG 918（0.5 μ M）分别显著降低和增加肝细胞中的ERY代谢。浓度-时间过程研究进一步证明，与细胞内N-去甲基-ERY对照曲线下面积（AUC）（0.795 +/- 0.057 μ M（.）min），AUC降低（0.513 +/- 0.028 μ M（.）min，p < 0.005），并且AUC（2.14 +/- 0.21 μ M（.）min，p < 0.05）。静脉推注研究的结果表明，与对照组的ERY清除率相比，（利福平组为47.2 +/- 12.5 ml/min/ kg，GG 918组为42.1 +/- 5.7），血液清除率降低，当共同施用利福平或GG 918时，分别观察到29.8 +/-6.1 ml/min/ kg（p < 0.05）和21.7 +/-9.0 ml/min/ kg（p < 0.01）。当任一抑制剂与ERY共同给药时，稳态分布容积不变，但t（1/2）和平均停留时间与对照组相比显著增加。肝脏摄取和外排转运蛋白调节ERY的细胞内浓度，从而影响代谢。在评价潜在的药物相互作用时，必须考虑转运蛋白和酶的相互作用。
The effects of hepatic uptake and efflux transporters on erythromycin (ERY) disposition and metabolism were examined by comparing results from rat hepatic microsomes, freshly isolated hepatocytes, and in vivo studies. Uptake studies carried out in freshly isolated rat hepatocytes showed that ERY and its metabolite (N-demethyl-ERY) are substrates of Oatp1a4 and Oatp1b2. Whereas rifampin and GG918 [ GF120918: N-{4-[ 2-(1,2,3,4- tetrahydro- 6,7-dimethoxy- 2- isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy9- oxo-4-acridine carboxamine] exerted minimal effects on metabolism in microsomes, rifampin (2.5 mu M) and GG918 (0.5 mu M) significantly decreased and increased ERY metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the intracellular N-demethyl-ERY control area under the curve (AUC) (0.795 +/- 0.057 mu M (.) min), a decreased AUC (0.513 +/- 0.028 mu M (.) min, p < 0.005) was observed when ERY was coincubated with rifampin, and an increased AUC (2.14 +/- 0.21 mu M (.) min, p < 0.05) was found when GG918 was present. The results of the i.v. bolus studies showed that, compared with the ERY clearance of the controls (47.2 +/- 12.5 ml/min/ kg for the rifampin group and 42.1 +/- 5.7 for the GG918 group), a decreased blood clearance, 29.8 +/- 6.1 ml/min/ kg (p < 0.05) and 21.7 +/- 9.0 ml/min/ kg (p < 0.01), was observed when rifampin or GG918, respectively, was coadministered. When either inhibitor was codosed with ERY, volume of distribution at steady state was unchanged, but t(1/2) and mean residence time significantly increased compared with the controls. Hepatic uptake and efflux transporters modulate intracellular concentrations of ERY, thereby affecting metabolism. The interplay of transporters and enzymes must be considered in evaluating potential drug-drug interactions.