Smeets Nori J L, Litjens Carlijn H C, van den Heuvel Jeroen J M W, van Hove Hedwig, van den Broek Petra, Russel Frans G M, Koenderink Jan B, de Wildt Saskia N
Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands.
Department of Pharmacy, Radboud Institute for Health Sciences, Center for Infectious Diseases, Radboud University Medical Center, 6525 EZ Nijmegen, The Netherlands.
Pharmaceutics. 2020 Sep 30;12(10):935. doi: 10.3390/pharmaceutics12100935.
Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters.
Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS.
Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520-770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters.
The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug-drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates.
依那普利常用于治疗心血管疾病。临床数据表明，依那普利的活性代谢产物依那普利拉的尿排泄由肾脏转运体介导。我们旨在确定依那普利拉对肾近端小管转运体的特异性。
使用过表达近端小管转运体的杆状病毒转导的HEK293细胞研究依那普利拉的细胞摄取。将其摄取到过表达基底外侧转运体OCT2、OAT1、OAT2或OAT3以及顶端转运体OAT4、PEPT1、PEPT2、OCTN1、OCTN2、MATE1、MATE2k和URAT1的细胞中的情况与模拟转导的对照细胞进行比较。使用囊泡测定法测试肾脏外排转运体MRP2、MPR4、P-糖蛋白和BCRP的转运情况。使用液相色谱-串联质谱法测量依那普利拉的浓度。
与对照细胞相比，依那普利拉摄取到表达OAT3以及OAT4的细胞中的量显著更高。依那普利拉对OAT3的亲和力为640（95%置信区间：520 -
