Decreased renal accumulation and toxicity of a new VCM formulation in rats with chronic renal failure.
We previously reported that MEEK, a generic product of vancomycin hydrochloride (VCM), was less nephrotoxic than a conventional preparation (S-VCM) in normal rats at a nephrotoxic dose (400 mg/kg) of VCM.(1)) To infer the clinical significance of this finding, we compared the risk of nephrotoxicity of these two formulations in rats with chronic renal failure in this study. MEEK or S-VCM was given intravenously to two weeks post-5/6 nephrectomy rats, and the pharmacokinetic profile of VCM and pathological evaluation were compared. There were no differences at the daily clinical dose (40 mg/kg), but at the twice the daily clinical dose (80 mg/kg), the mean plasma concentration of VCM was higher after S-VCM administration than after MEEK and the CL(tot) and CL(r) decreased to approximately 60% of those after MEEK. The renal tissue concentration of VCM was 1.5-fold higher at 24hr after S-VCM administration than after MEEK. Pathologically, no marked differences between the findings were observed at 24hr after administration of each formulation. These findings suggest that MEEK reduces renal damage caused by VCM and prevents the iatrogenic aggravation of nephrotoxicity. These results hold out hope that MEEK will permit high-dose administration of VCM, while revealing clinical significance of the nephrotoxicity-reduction by MEEK.
Hodoshima
Naoko
N
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan.
Masuda
Satohiro
S
Inui
Ken-Ichi
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016568:Drugs, Generic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014640:Vancomycin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D016568:Drugs, Generic; D014640:Vancomycin