[Prevention of cisplatin induced nephrotoxicity by administering urinastatin to rabbits--comparison with other protease inhibitors].
The present study was performed to evaluate the mechanism of the protective effect of urinastatin (US) against cisplatin (CDDP) induced nephrotoxicity. We measured consecutively the change in the creatinine clearance (Ccr) level, urinary arylamidase (AA) activity, and urinary gamma-glutamyl transpeptidase (gamma-GTP) activity as the indices of nephrotoxicity. These drugs such as US (10,000 U/kg, 3h: group 1), gabexate mesilate (2mg/kg/h, 4h: group 2), and aprotinin (5,000 U/kg/h, 4h: group 3) as protease inhibitors, and dopamine HCl (0.3mg/kg/h, 4h: group 4) for the increase in renal blood flow were used with the hydration of 15 ml/kg/h during 4 hours of experiments on rabbits. The change in the Ccr value after the intravenous administration of CDDP indicated that the level in groups 3, 4 decreased significantly at one day after the administration of CDDP. On the other hand, there was little significant increase in urinary AA activity and/or urinary gamma-GTP activity in group 1, while a transitional increase was observed in groups 2, 3, and 4, among which the highest level was found in group 4. These results are attributed to the protective action of US against CDDP mainly in the inhibition of the lysosomal enzyme released by the destruction of lysosomes in the proximal tubule cells of the kidney.
Kobayashi
H
H
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine.
Ohi
H
H
Kawashima
Y
Y
D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000652:urine; D000818:Animals; D007611:Aprotinin / Q000627:therapeutic use; D002945:Cisplatin / Q000009:adverse effects*; D003404:Creatinine / Q000378:metabolism; D004298:Dopamine / Q000627:therapeutic use; D016670:Gabexate; D006023:Glycoproteins / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000652:urine
D006023:Glycoproteins; D006146:Guanidines; D011480:Protease Inhibitors; D016670:Gabexate; D007611:Aprotinin; D003404:Creatinine; D005723:gamma-Glutamyltransferase; D000626:Aminopeptidases; C028665:urinastatin; D002945:Cisplatin; D004298:Dopamine