Читать книгу Drug Transporters - Группа авторов - Страница 97

Acute and chronic renal disease is a significant cause of morbidity and mortality and have been associated with the altered clearance of drugs and toxicants. In rodents, acute and chronic kidney disease can be recapitulated experimentally using surgical nephrectomy, ischemia‐reperfusion injury, and toxicant‐induced damage. Nephrectomy, or 5/6 removal of kidney tissue, mirrors clinical features of chronic renal disease including elevated circulating creatinine and BUN levels. In rats that have undergone 5/6 nephrectomy, the secretion of cimetidine is markedly reduced, which coincided with lower expression of rMate1 [82]. Similarly, ischemic injury can be accomplished within rats by clamping pedicles for a short period of time and then releasing the clamps and re‐establishing blood flow to the kidneys. This results in ischemic‐reperfusion injury as evidenced by elevations in BUN and serum creatinine levels. In rats that have undergone ischemia‐reperfusion injury, the plasma clearance of the antihistamine famotidine and the probe cation TEA are markedly reduced [83]. Compared with sham‐operated rats, expression of Oct2 and Mate1 proteins were decreased by more than 50% in rats with ischemia‐reperfusion injury [83]. As a result, the impaired clearance is likely due to both diminished uptake by Oct1 and 2 transporters and disrupted efflux by MATE transporters, as well as change in filtration.

Acute kidney injury caused by the cancer drug cisplatin increases BUN and serum creatinine levels and leads to loss of proximal tubules. In rats treated with a toxic dose of cisplatin, there is downregulation of rOct2 and rMate1 protein [84]. Interestingly, the uremic toxin indoxyl sulfate appears to play a role in the reduced levels of both cation transporters as treatment with AST‐120, an adsorbent, partially restored expression of rOct2 and rMate1 protein, as well as improved renal function indicators [84].