Stability of New Carbapenem DA-1131 to Renal Dipeptidase (Dehydropeptidase I)

Abstract

The stability of DA-1131 to renal dipeptidase (RDPase) (EC 3.4.13.19) was compared with that of imipenem and meropenem by V max /K m ratios as an index of the enzyme's preference for substrates. Our results showed a decreasing order of imipenem (6.24), meropenem (2.41), and DA-1131 (1.39). The biochemical evaluation of DA-1131 as the least preferred substrate of RDPase suggests its potential use as a novel ␤-lactam antibiotic which may be usable without coadministration of RDPase inhibitors once its clinical suitability is proven.Imipenem (N-formimidoylthienamycin), developed by Merck Sharp & Dohme, West Point, Pa., was highly effective against bacterial species resistant to most ␤-lactam antibiotics with unusually high potency against gram-positive as well as gramnegative bacteria (8,21,23). It is degraded, though, in the kidneys of various animals, resulting in a reduced antibacterial activity. The enzyme responsible for this metabolism was shown to be renal dipeptidase (RDPase, also called renal dehydropeptidase I) (EC 3.4.13.19) located in the brush-border membrane of renal proximal tubules (8,9,20). Cilastatin, Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-butenoic acid, is a specific competitive inhibitor of RDPase and is well matched in its pharmacokinetic properties for coadministration with imipenem (8,22). Therefore, imipenem is designed to be coadministered with cilastatin to suppress RDPase for its clinical use, and they are now manufactured in a 1:1 combination.Meropenemhept-2-ene-2-carboxylic acid, which was introduced in the late 1980s, though relatively less active against gram-positive bacteria than imipenem (1,4,6,7), is stable in the presence of RDPase as judged by its V max /K m ratio. Thus, it is currently in clinical use without coadministration of an RDPase inhibitor.DA 237, 1996). DA-1131 has been examined in many aspects, including pharmacokinetics under various conditions in animals (10,12,13,16,17,18,19), in the renal excretion mechanism (14, 15), and in nephrotoxicity-related studies (11).We measured the kinetic parameters of imipenem, meropenem, and DA-1131 in relation to human RDPase and the RDPases of various animals to examine the stability of DA-1131 in reference to the two well-established ␤-lactam antibiotics, imipenem and meropenem.DA-1131 and meropenem were supplied by Dong-A Research Laboratory. Imipenem and cilastatin were obtained from Merck Sharp & Dohme. Human RDPase was purified to homogeneity with a 2,029-fold purification, and RDPases from animal sources were purified or partially purified according to the method previously described (24).RDPase-catalyzed hydrolysis of imipenem, meropenem, and DA-1131 was measured in the presence and absence of cilastatin (0.15 M) according to the method described by Kim and Campbell (9) by measuring the decrease in absorbance at 298 nm and 37°C as a function of time for 2.5 min. Substrate concentration was varied over a range of 1.25 to 3.3 mM in 3-(N-morpholino)propanesulfonic acid, pH 7.1. One microgram of purified RDPase was employ...

Structure, Mechanism, and Substrate Profile for Sco3058: The Closest Bacterial Homologue to Human Renal Dipeptidase,

“…This enzyme is also able to catalyze the hydrolysis of leukotriene D 4 ,, as well as the oxidized degradation product of glutathione, l -Cys-Gly − . Human renal dipeptidase (hRDP) is the only enzyme in humans that has been shown to catalyze the hydrolysis of β-lactams such as SCH 29482, imipenem, meropenem, and DA-1131 , . However, dipeptides are consistently better substrates for hRDP than are β-lactams ,, .…”

Novel prodrugs of meropenem with two lipophilic promoieties: synthesis and pharmacokinetics

“…Imipenem and panipenem are unstable chemically and to renal dehydropeptidase-I, and are thus used in combination with cilastatin and betamipron, respectively. MEPM and doripenem have a 1b-methyl group, and are stable against chemical degradation and hydrolysis by dehydropeptidase-I, [7][8][9] and are thus used without cilastatin or betamipron.…”