Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: in vitro and in vivo studies.
Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: in vitro and in vivo studies.
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DOI：
10.1111/j.1530-0277.2007.00551.x
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发表时间：
2007-11
期刊：
影响因子：
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通讯作者：
Scott J. Fisher;I. Lee;P. Swaan;N. Eddington
中科院分区：
文献类型：
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作者：
Scott J. Fisher;I. Lee;P. Swaan;N. Eddington
背景饮酒及其后续代谢对药物转运、吸收和药代动力学的影响知之甚少。本研究检测了乙醇代谢产物乙醛对临床相关药物转运蛋白PEPT 1的影响。乙醇的代谢和随后的乙醛形成被认为调节胃肠道内PEPT 1对多种临床上重要的拟肽药物化合物的摄取能力。方法以非水解性PEPT 1特异性底物甘氨酰肌氨酸（[（3）H]-GlySar）为研究对象。在Caco-2和中国仓鼠卵巢（CHO）-hPEPT 1细胞模型中进行了体外摄取研究，在存在乙醛的情况下，测量标记化合物相对于增加水平的未标记化合物的细胞摄取。在经口给予乙醇/双硫仑（5 g/kg / 100 mg/kg）6天的雄性Sprague-Dawley大鼠中测量[（3）H]-GlySar的体内吸收。将这些结果与用盐水、单独的乙醇或单独的双硫仑处理的对照大鼠进行比较。结果与未处理对照组相比，用1 mM乙醛处理的CHO-hPEPT 1细胞中[（3）H]-GlySar的体外摄取显著降低（p < 0.05）。与未处理的对照细胞相比，用1 mM乙醛处理的Caco-2细胞单层中[（3）H]-GlySar的摄取也显著降低。通过AUC（0-12小时）测量，与对照大鼠组相比，乙醇处理大鼠中[（3）H]-GlySar的体内吸收降低约50%。结论乙醛对PEPT 1寡肽转运蛋白转运的治疗药物化合物的摄取和生物利用度的影响尚未被记录。在目前的研究中，我们证明，乙醛显着调节PEPT 1功能，从而影响药物的生物利用度。据我们所知，这是第一份关于乙醇代谢产物对胃肠道底物吸收的影响的报告，而不是在肝脏中的相互作用，这是酒精病理生理学研究的一个代表性不足的领域。
BACKGROUND The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. This study examines the effects of the ethanol metabolite, acetaldehyde, on the clinically relevant drug transporter, PEPT1. The metabolism of ethanol and the following acetaldehyde formation is thought to modulate the uptake capacity of PEPT1 within the gastrointestinal tract for a variety of clinically important peptidomimetic drug compounds. METHODS Glycylsarcosine ([(3)H]-GlySar), a nonhydrolysable PEPT1 specific substrate was used in our studies. In vitro uptake studies were performed in the Caco-2 and Chinese hamster ovary (CHO)-hPEPT1 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [(3)H]-GlySar was measured in male Sprague-Dawley rats that were treated with oral dose of ethanol/disulfiram (5 g/kg / 100 mg/kg) for 6 days. These results were compared to control rats treated with saline, ethanol alone or disulfiram alone. RESULTS In vitro uptake of [(3)H]-GlySar in CHO-hPEPT1 cells treated with 1 mM acetaldehyde was significantly decreased (p < 0.05) as compared to untreated controls. The uptake of [(3)H]-GlySar in Caco-2 cell monolayers treated with 1 mM acetaldehyde was also significantly decreased as compared to the untreated control cells. In vivo absorption of [(3)H]-GlySar in ethanol treated rats, as measured by AUC(0-12 hours) were decreased by approximately 50% versus the control rat group. CONCLUSION The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and, thereby, affects drug bioavailability. To our best knowledge, this is the first report on the effects of an ethanol metabolite on substrate absorption in the gastrointestinal tract, rather than interactions in the liver, which is an under-represented area of research in alcohol pathophysiology.