Читать книгу Drug Transporters - Группа авторов - Страница 41

Oct2 ^−/− mice are viable and fertile, showing no apparent physiological defects [42]). However, because Oct1 is also highly expressed in rodent kidney, it has been necessary to generate Oct1/2 ^−/− double‐knockout mice as a model for the effect of OCT2 on renal drug clearance in humans. The Oct1/2 ^−/− mice, as with each of the single‐knockouts, is compatible with normal physiology (i.e., normal viability, fertility, and lifespan are observed, with no apparent physiological abnormalities) [42]. However, unlike the single‐knockouts, Oct1/2 ^−/− mice show significant impairment in the active tubular secretion of organic cations in the kidney. Specifically, renal tubular secretion of TEA is effectively abolished in Oct1/2 ^−/− mice, with renal clearance approximating glomerular filtration [42]. Consequently, these mice exhibit significantly elevated plasma levels of TEA compared with wild‐type or Oct1 ^−/− single‐knockout mice. After steady‐state infusion of TEA, plasma levels are elevated approximately 6‐fold in the Oct1/2 ^−/− double‐knockout mice compared to Oct1 ^−/− , Oct2 ^−/− , or wild‐type mice [42]. In mice, OCT1/OCT2 deficiency or coadministration of OCT2 inhibitors (e.g., cimetidine) protects from cisplatin‐induced nephrotoxicity [43].