Carbapenems, nephrotoxicity

In addition to variable chemical stabiUty the carbapenems are susceptible to P-lactam cleavage by a dehydropeptidase en2yme (DHP-I) located on the bmsh borders of the kidney (53). Clinically, MK 0787 (18) is used with an inhibitor of this en2yme, cil a sta tin [78852-98-9] (MK 0791) (34), 16 26 2 5 dramatic effect not only on the urinary recovery of the drug, but also reduces any nephrotoxic potential (52) (see Enzyme... 

In an earlier study of the effects of imipenem in the rabbit kidney it was shown that imipenem caused a significant decrease of mitochondrial respiration, deplehon of reduced glutathione, increased production of oxidized glutathione and lipid peroxidation [56]. However, these effects were less than those produced by a comparable nephrotoxic dose of cephaloridine [56]. Panipenem induced nephrotoxicity at a dose of 200 mg/kg, i.v., but this was less severe than that caused by a single dose of imipenem [57]. Simultaneous adminis-trahon of p-mipron (N-benzoyl-3-propionic acid) with imipenem and panipenem reduced the nephrotoxicity of these carbapenems by inhibiting the active transport of carbapenems in the renal cortex [57]. 

The differences in nephrotoxicity of carbapenems are due to the different structural features, especially the physicochemical properties. The structure of meropenem differs from the structure of imipenem and panipenem due to the presence of a ip-methyl group and the lesser basicity of the amino group in the C-2 side chain. The basicity of meropenem is much lower than that of imipenem and panipenem [70]. The reduced meropenem nephrotoxicity is not related to the presence of the ip-methyl group. However, the basicity of the C-2 side chain of carbapenems is important for... 

Hirouchi Y, Naganuma H, Kawahara Y, Okada R, Kammiya A, Inui K, Hori R. Preventive effect of Bmipron on nephrotoxicity and uptake of carbapenems in rabbit renal cortex. Jpn J Pharmacol 1994 66(1) 1-6. 

Nouda H, Matsumura H,TanioT, Sunagawa M. Structural feature of carbapenem compounds or nephrotoxicity effect of C-2 side chain. J Antibiotics 1996 49(6) 603-606. 

Imipenem, a carbapenem antimicrobial, also possesses nephrotoxic potential. In animal models, nephrotoxicity is dose dependent and characterized by tubular necrosis. Interestingly, imipenem nephrotoxicity is markedly attenuated by co-administration of cilastatin, an inhibitor of the cytosolic and brush border enzyme dehydropeptidase I (DHP). Although DHP is responsible for hydrolyzing imipenem to inactive metabolites, the major protective effect of cilastatin appears to be due to inhibition of renal imipenem accumulation rather than DHP inhibition. 

The strained structure of carbapenems confers a higher reactivity to the carbapenem skeleton than that of cephalosporin skeleton. It has been suggested that both P-lactam ring and the basicity of C-2 side play a major role in carbapenem-induced nephrotoxicity [70]. 

It has been suggested that mitochondrial injury may mediate, at least in part, the nephrotoxicity of some P-lactams [67]. Mitochondrial respiration with and uptake of succinate after exposure to toxic doses of cephaloridine, cephaloglycin, or imipenem [98] showed significant reduction of both functions. Cephalexin did not affect either the mitochondrial uptake or respiration with succinate. Depressed mitochondrial respiration secondary to acylation of the mitochondrial transporter for succinate appears to be implicated in renal toxicity caused by cephalosporins and carbapenems [98]. The organic anion fluorescein accumulates in mi-... 

The use of piperacillin is reported to be a risk factor for aminoglycoside-associated nephrotoxicity. A reduction in serum aminoglycoside levels can occur if aminoglycosides and penicillins are given together to patients with severe renal impairment. No pharmacokinetic interaction of importance appears to occur with intravenous aminoglycoside and penicillins in those with normal renal function or between aminoglycosides and carbapenems. The serum levels of oral phenoxymethylpenicillin can be halved by oral neomycin. 

In 1993, panipenem from Sankyo obtained approval in Japan. This drug is also nephrotoxic. Concurrent administration of betamipron blocks the transport of organic anions, whereby the toxicity of panipenem is reduced. Both first-generation carbapenem drugs possess the regular carbapenem scaffold, and a strongly basic residue in the side-chain at C-2. 

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