Akarawut W, Lin C J, Smith D E
College of Pharmacy and Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan, USA.
J Pharmacol Exp Ther. 1998 Nov;287(2):684-90.
Angiotensin converting enzyme (ACE) inhibitors are important therapeutic agents for treating patients with hypertension and cardiovascular diseases. Although most ACE inhibitors are cleared by the kidney via glomerular filtration and tubular secretion, little is known about their reabsorption potential. In particular, it is believed that while certain ACE inhibitors are transported by the intestinal peptide transporter (PepT1), these same compounds do not interact with the renal peptide transporter (PepT2). In the present study, we examined the interaction of quinapril with the high-affinity peptide transporter, PepT2. Studies were performed in rabbit renal brush border membrane vesicles in which the uptake of [14C]glycylsarcosine (GlySar), at low substrate concentrations, was examined in the absence and presence of quinapril (and other ACE inhibitors). We found that quinapril was capable of cis-inhibiting the uptake of GlySar and in a concentration-dependent manner. While the Ki for quinapril ( approximately 1 mM) was several-fold higher than the Km for GlySar ( approximately 160 microM), the interaction was unique in that inhibition of PepT2 was of a noncompetitive type. Overall, the data suggest that quinapril is a low-affinity inhibitor of the renal peptide transporter and that it binds to a site distinct from that of the GlySar binding site.
血管紧张素转换酶（ACE）抑制剂是治疗高血压和心血管疾病患者的重要治疗药物。尽管大多数ACE抑制剂通过肾小球滤过和肾小管分泌经肾脏清除，但对其重吸收潜力知之甚少。特别是，人们认为某些ACE抑制剂虽由肠道肽转运体（PepT1）转运，但这些化合物与肾脏肽转运体（PepT2）不相互作用。在本研究中，我们检测了喹那普利与高亲和力肽转运体PepT2的相互作用。研究在兔肾刷状缘膜囊泡中进行，在低底物浓度下，于不存在和存在喹那普利（及其他ACE抑制剂）的情况下检测[14C]甘氨酰肌氨酸（GlySar）的摄取。我们发现喹那普利能够顺式抑制GlySar的摄取，且呈浓度依赖性。虽然喹那普利的Ki（约1 mM）比GlySar的Km（约160 microM）高几倍，但这种相互作用的独特之处在于对PepT2的抑制属于非竞争性类型。总体而言，数据表明喹那普利是肾脏肽转运体的低亲和力抑制剂，且它与GlySar结合位点不同的位点结合。
