Renal dehydropeptidase I DHP

Bicyclic-P-lactams Antibacterial and highly stable to porcine renal dehydropeptidase-I (DHP-I)... 

Recently, Kang et al. [67] have found that the bicyclic P-lactams (XVI) exhibit potent antibacterial activities against a wide range of Gram-(+) and Gram-(—) bacteria and high stability to the renal dehydropeptidase-I (DHP-I). Mikamo et al. [68] have reported in vitro and in vivo antibacterial activity of bicyclic p-lactam... 

The first carbapenem released for clinical use was imipenem (5.46), a compound with relatively high resistance to microbial /3-lactamases. The addition of the (iminomethyl)amino side chain renders imipenem chemically more stable than thienamycin. But, like thienamycin, imipenem is also easily hydrolyzed by renal dehydropeptidase I, producing a mixture of /3-lactam ring-opened 1-pyrrolidine epimers at C(3) [161], The renal metabolism of imipenem can be minimized by co-administration of cilastatin (5.53), a competitive inhibitor of DHP-I [15 6] [162],... 

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. 

Like carbapenems, several penems have also been found to be susceptible to renal dehydropeptidase degradation [165-167], 6-Substituted methyl-idene-penems 5.56 are very potent broad-spectrum inhibitors of bacterial /3-lactamase, with the inhibitory activity residing predominantly in the (5R)-enantiomers. As a rule, the (5S)-enantiomers are less stable than the (5R)-enantiomers toward DHP-I [168],... 

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