Hodoshima Naoko, Masuda Satohiro, Inui Ken-Ichi
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto, Japan.
Drug Metab Pharmacokinet. 2007 Dec;22(6):419-27. doi: 10.2133/dmpk.22.419.
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.
我们之前报道过，美克（MEEK）作为盐酸万古霉素（VCM）的一种通用产品，在给予VCM肾毒性剂量（400mg/kg）时，对正常大鼠的肾毒性低于传统制剂（S-VCM）。（1）为了推断这一发现的临床意义，我们在本研究中比较了这两种制剂在慢性肾衰竭大鼠中的肾毒性风险。将MEEK或S-VCM静脉注射给5/6肾切除术后两周的大鼠，并比较VCM的药代动力学特征和病理评估。在每日临床剂量（40mg/kg）时没有差异，但在每日临床剂量的两倍（80mg/kg）时，S-VCM给药后VCM的平均血浆浓度高于MEEK给药后，并且CL（tot）和CL（r）降至MEEK给药后的约60%。S-VCM给药后24小时，VCM的肾组织浓度比MEEK给药后高1.5倍。在病理上，每种制剂给药后24小时观察到的结果之间没有明显差异。这些发现表明，MEEK可减轻VCM引起的肾损伤，并防止医源性肾毒性加重。这些结果让人希望MEEK将允许高剂量使用VCM，同时揭示MEEK降低肾毒性的临床意义。
