Cilastatin (MK0791)

Cilastatin (MK0791) is a reversible, competitive renal dehydropeptidase I (DHP-I) inhibitor with an IC₅₀ of 0.1μM in vitro. Cilastatin is an antibacterial adjunct that inhibits the metallob-lactamase enzyme CphA and membrane dipeptidase (MDP) of bacteria with an IC₅₀ of 178±11μM and 0.3±0.01μM, respectively^[1,2]. Cilastatin shows protective effect against acute kidney injury caused by vancomycin-induced nephrotoxicity^[3,4].

In vitro, Cilastatin (0.5μg/ml; up to 24h) inhibits the growth of a broad spectrum of both gram-positive and gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae et.al with a lower IC₅₀ compares to Imipenem, Ciprofloxacin, Amikacin, Ceftazidime, and Piperacillin^[2]. Cilastatin (200µg/mL; 24h) shows a nephroprotective effect against gentamicin-induced renal injury without altering the bactericidal efficiency of gentamicin in vitro with a renal proximal tubular primary cell model^[5]. Imipenem/Cilastatin (IPM/CS) (7.25mg/ml) combination demonstrates an embolic effect with a particle analysis^[6].

In vivo, Cilastatin (150mg/kg/day; 7 days; i.p) attenuates vancomycin-induced nephrotoxicity via P-glycoprotein^[7]. Cilastatin (200mg/kg; retroorbital injection) administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by a megalin deletion in a C57BL/6-based in vivo research^[8].

References:
[1] Keynan, S et al. “The renal membrane dipeptidase (dehydropeptidase I) inhibitor, cilastatin, inhibits the bacterial metallo-beta-lactamase enzyme CphA.” *Antimicrobial agents and chemotherapy* vol. 39,7 (1995): 1629-31. doi:10.1128/AAC.39.7.1629
[2] Petersen, P J et al. “In vitro and in vivo activities of LJC10,627, a new carbapenem with stability to dehydropeptidase I.” *Antimicrobial agents and chemotherapy* vol. 35,1 (1991): 203-7. doi:10.1128/AAC.35.1.203
[3] Humanes, Blanca et al. “Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity.” *BioMed research international* vol. 2015 (2015): 704382. doi:10.1155/2015/704382
[4] González-Nicolás, María Ángeles, and Alberto Lázaro. “Cilastatin, a new therapeutic promise for acute kidney injury.” *Kidney international* vol. 106,4 (2024): 560-562. doi:10.1016/j.kint.2024.07.024
[5] Jado, Juan Carlos et al. “Nephroprotective Effect of Cilastatin against Gentamicin-Induced Renal Injury In Vitro and In Vivo without Altering Its Bactericidal Efficiency.” *Antioxidants (Basel, Switzerland)* vol. 9,9 821. 3 Sep. 2020, doi:10.3390/antiox9090821
[6] Nakamura, Hiroki et al. “In vitro study of the embolic characteristics of imipenem/cilastatin particles.” *CVIR endovascular* vol. 7,1 27. 11 Mar. 2024, doi:10.1186/s42155-024-00441-x
[7] Im, Dai Sig et al. “Cilastatin attenuates vancomycin-induced nephrotoxicity via P-glycoprotein.” *Toxicology letters* vol. 277 (2017): 9-17. doi:10.1016/j.toxlet.2017.05.023
[8]Matsushita, Katsuyuki et al. “Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice.” *Journal of the American Society of Nephrology : JASN*vol. 32,10 (2021): 2579-2594. doi:10.1681/ASN.2020030263

Cilastatin (MK0791)是一种可逆的竞争性肾脱氢肽酶-I （DHP-I）抑制剂，体外IC₅₀为0.1μM。Cilastatin是一种抗菌辅料，对细菌的金属内酰胺酶CphA和膜二肽酶（MDP）具有抑制作用，IC₅₀分别为178±11μM和0.3±0.01μM^[1,2]。Cilastatin对万古霉素所致肾毒性急性肾损伤有保护作用^[3,4]。

在体外研究中，Cilastatin（0.5μg/ml；作用最高24h）可抑制广谱革兰氏阳性和革兰氏阴性细菌的生长，如大肠杆菌、肺炎克雷伯菌、阴沟肠杆菌等，与亚胺培南、环丙沙星、阿米卡星、头孢他啶和哌拉西林相比Cilastatin的IC₅₀更低^[2]。Cilastatin(200µg/mL；24h)在体外肾近端小管原代细胞模型中显示出庆大霉素对肾损伤的肾保护作用，但不改变庆大霉素的杀菌效果^[5]。Imipenem/Cilastatin（IPM/CS）（7.25mg/ml）组合在颗粒分析中表现出具有栓塞作用^[6]。

体内，Cilastatin(150mg/kg/天；7天；皮下注射）通过P-glycoprotein减弱万古霉素引起的肾毒性^[7]。Cilastatin(200mg/kg；眼眶后注射)引起选择性蛋白尿和管状肌红蛋白摄取抑制，类似于基于C57BL/6的体内研究中meggalin缺失所引起的结果^[8]。