Structural Eeatures of Carbapenem Compounds for Nephrotoxicity: Effect of C-2 Side Chain.

Abstract

Several jS-lactam antibiotics produce acute nephrotoxicity in both human and laboratory animals1~3). Two clinically available carbapenems, imipenem (IPM) and panipenem (PAPM), are also nephrotoxic in laboratory animals when each carbapenem is administered without the combinational drug (i.e. cilastatin and betamipron, respectively)4'5). The nephrotoxicity of these carbapenem antibiotics is characterized by necrosis of the proximal tubule epithelial cells, similar to the well known nephrotoxic cephalosporin, cephaloridine (CER). Meropenem (MEPM), a new dehydropeptidase-I (DHP-I) stable carbapenem antibiotic without neurotoxicity6'7), has shown only minimal nephrotoxicity at a very high dose in laboratory animals8). This profile could make it the first carbapenem that does not need any combinational drug. The structure of MEPM is different from that of IPM and PAPMby the presence of a 1/5-methyl group and the lesser basicity of the amino group in the C-2 side chain. The basicity of MEPMis much lower than that ofIPM and PAPM (pKa=7.49), 9.91O), 10.911}, respectively), so that the physico-chemical properties of MEPM are different from those of the others.

Recent advances in carbapenem chemistry (review)

“…As a result, the first-generation carbapenem antibiotic, imipenem (2), was launched in the middle of the 1980s as a coadministered drug with cilastatin (3), which inhibits the degradation by DHP-I and decreases the nephrotoxicity. Panipenem (4), which had a similar profile to 3, was also developed in Japan as a coadministered drug with an inhibitor against the organic anion transportation, betamipron (5). In the middle of the 1990s, the second-generation carbapenem (llJ-methylcarbapenem [6]) meropenem (6) had arrived as a prominent drug, as it was the first drug which could be utilized as a single agent without any coadministered drugs.…”

“…Efficient synthetic methodologies toward carbapenem derivatives were established and a variety of carbapenems were prepared. Their structure-activity relationships (SAILs) (see review [2]) concerning not only the antibacterial activities, the metabolic degradation by renal dehydropepfidase-I (DHP-I) [3], and chemical stability but also the side effects such as nephrotoxicity [4] and neurotoxicity [5], have been widely studied to improve the advantages of 1 and to overcome its shortcomings such as physicochemical instability, metabolic instability versus DHP-I, nephrotoxicity, and neurotoxicity for clinical use. As a result, the first-generation carbapenem antibiotic, imipenem (2), was launched in the middle of the 1980s as a coadministered drug with cilastatin (3), which inhibits the degradation by DHP-I and decreases the nephrotoxicity.…”