Renal tolerance of imipenem/cilastatin and other beta-lactam antibiotics in rats.
Imipenem is inactivated by the renal dehydropeptidase I, which can be inhibited by cilastatin. Therefore, both compounds are administered in combination. According to the manufacturers, they are not nephrotoxic in rats. 70 female Wistar rats (n = 10/test series) were treated over five days at dosage intervals of 12 hours with intraperitoneal injections (injection volume: 10 ml/200 g body weight) of isotonic 0.9% NaCl, cilastatin (1000 mg/kg/day), imipenem (500 and 1000 mg/kg/day), cilastatin + imipenem (500 or 1000 mg/kg/day each) and cefsulodin (1000 mg/kg/day). The nocturnal excretion of renal tubular cells was determined. Furthermore, three rats in each test were treated intraperitoneally with 150 mg/kg imipenem or with the combination of imipenem and cilastatin (150 mg/kg each). Imipenem concentrations were measured over four hours in the blood of the tail vein. Commencing on the second day of study, cilastatin, imipenem and the combination of both substances induced significant surplus excretion of tubular cells compared to the control group. The tubulotoxic effects of imipenem and imipenem + cilastatin in combination were dose-dependent. The toxic effects of imipenem, imipenem + cilastatin and cefsulodin did not significantly differ. Cilastatin prolonged the half-life of imipenem in the blood from 0.4 to 0.9 h and increased the AUC of imipenem from 156 to 325 mg/l/h.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000633:toxicity*; D015377:Cilastatin; D003521:Cyclopropanes / Q000008:administration & dosage / Q000633:toxicity*; D004338:Drug Combinations; D004361:Drug Tolerance; D005260:Female; D015378:Imipenem; D007684:Kidney Tubules / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013845:Thienamycins / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D003521:Cyclopropanes; D004338:Drug Combinations; D013845:Thienamycins; D015377:Cilastatin; D015378:Imipenem