Influence of grapefruit juice on the pharmacokinetics of diltiazem in Wistar rats upon single and multiple dosage regimens.
Influence of grapefruit juice on the pharmacokinetics of diltiazem in Wistar rats upon single and multiple dosage regimens.
复制标题
DOI：
--
复制
发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
S. P. Boddu;M. Yamsani;S. Potharaju;S. Veeraraghavan;S. Rajak;S. Kuma;B. Avery;M. Repka;V. Varanasi
中科院分区：
文献类型：
--
作者：
S. P. Boddu;M. Yamsani;S. Potharaju;S. Veeraraghavan;S. Rajak;S. Kuma;B. Avery;M. Repka;V. Varanasi
肠道p -糖蛋白（P-gp）的药物外排被认为是除细胞色素P450 3A酶外影响许多药物口服吸收的重要生化屏障。关于葡萄柚汁（GFJ）对P-gp介导的药物外排的影响，已经发表了各种相互矛盾的报道，其中GFJ已被证明没有影响，作为抑制剂作用或酶的激活。因此，本研究的目的是澄清先前的研究结果，采用双向方法，包括单剂量和多剂量方案。一组雄性Wistar大鼠（n = 6）给予地尔硫卓（DTZ） 15 mg/kg，同时给予GFJ 5 ml/kg，另一组（n = 6）给予含有DTZ的蒸馏水（对照组）。第三组大鼠口服GFJ 6天，第7天同时给予GFJ和DTZ。多剂量GFJ可显著降低DTZ的Cmax和AUC。这些数据在单剂量GFJ同时治疗的情况下也有所下降。通过体外代谢研究和肠囊实验了解其作用机制。在多剂量GFJ处理的大鼠肝脏S9组分中，与对照组相比，DTZ代谢显著增加。此外，与对照组相比，GFJ处理的大鼠从十二指肠转运的药物量减少（分别为1581.0 +/- 7.8 nM和1084.81 +/- 6.1 nM）。据报道，葡萄柚汁还能抑制有机阴离子运输多肽（OATP），这是一种内流转运体，从而降低了OATP底物的血液水平，这在体外研究中是显而易见的。在OATP特异性抑制剂普伐他汀（1581.0 +/- 7.8 nM至1265.0 +/- 5.5 nM）的作用下，药物从十二指肠转运的量减少。口服单剂量GFJ对P-gp无影响，而多剂量GFJ可提高P-gp表达水平，降低OATP水平，从而对大鼠肠道吸收产生不同程度的影响，从而克服对DTZ代谢的抑制。
Drug efflux by intestinal P-glycoprotein (P-gp) is recognized as a significant biochemical barrier affecting oral absorption for a number of drugs apart from the cytochrome P450 3A enzyme. Various conflicting reports have been published regarding the effects of grapefruit juice (GFJ) on P-gp mediated drug efflux, in which GFJ has been shown to have no effect, as an inhibitor effect or activation of the enzyme. Therefore the present study's objective was to provide clarification of previous findings, adopting a two-way approach, involving both single dose and multiple dosage regimens. Diltiazem (DTZ) 15 mg/kg was administered concomitantly with 5 ml/kg of GFJ to one group (n = 6) of male Wistar rats and another group (n = 6) of animals were provided distilled water with DTZ (the control). A third group of rats was administered GFJ orally for six days and on seventh day GFJ and DTZ were administered concomitantly. The Cmax and AUC of DTZ were decreased significantly in the presence of multiple dose treatment of GFJ. These data were also decreased in presence of simultaneous treatment of single dose GFJ. In vitro metabolism studies and gut sac experiments were conducted in order to understand the mechanism involved. In the liver S9 fraction prepared from the rats treated with multiple doses of GFJ, DTZ metabolism was significantly increased compared to the control. Furthermore, the amount of drug transported from the duodenum was reduced in GFJ treated rats compared to that of the control (1581.0 +/- 7.8 nM vs 1084.81 +/- 6.1 nM, respectively). Grapefruit juice was also reported to inhibit the organic anion transporting polypeptide (OATP), an influx transporter thus reducing the blood levels of OATP substrates which was evident from the in vitro studies. The amount of drug transported from the duodenum was reduced in the presence of pravastatin, a specific OATP inhibitor (1581.0 +/- 7.8 nM to 1265.0 +/- 5.5 nM). Oral single dose exposure to GFJ showed no effect on P-gp, whereas multiple dose administration of GFJ resulted in increased levels of P-gp expression and decreased levels of OATP, thus showing a varied effect on intestinal absorption, and therefore overcoming the inhibition of DTZ metabolism in rats.