Kidney dehydropeptidase

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

In the last 25 years, various natural carbapenems have been discovered (1). However, their potential is limited by chemical instability. Imipenem (N-formimidoylthienamycin), the first carbapenem in use, is therefore a stabilized synthetic compound. To overcome a second difficulty, namely inactivation by a kidney dehydropeptidase, imipenem has to be combined with cilastatin, a competitive inhibitor of that enzyme. Meropenem has better stability in the presence of renal dehydropeptidase I (2). The... 

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... 

Mechanism of Action A fixed-combination carbapenem. Imipenem penetrates the bacterial cell membrane and binds to penicillin-binding proteins, inhibiting cell wall synthesis. Cilastatin competitively inhibits the enzyme dehydropeptidase, preventing renal metabolism of imipenem. Therapeutic Effect Produces bacterial cell death. Pharmacokinetics Readily absorbed after IM administration. Protein binding 13%-21%. Widely distributed. Metabolized in the kidneys. Primarilyexcreted in urine. Removed by hemodialysis. Half-life 1 hr (increased in impaired renal function). 

In humans, imipenem was foimd to be metabolized by an enzyme in the kidney, renal dehydropeptidase-I, which acts as a P-lactamase. Since the enzyme appears to serve no essential role in human metabolism, scientists were able to develop a synthetic competitive inhibitor, cilastatin, which they then used with imipenem to produce the combination drug, primaxin (Tienam). Primaxin was introduced into medical practice in 1985. 

Of the many derivatives prepared, BRL 42715 (31) was the compound with the best overall activity and stability. The enzyme, renal dehydropeptidase I (RDHP) is known to be a major cause of metabolic inactivation of carbapenems, such as imipenem, and penems. Whereas the ethylidene derivative (90c) showed substantial degradation of the biologically active (5R)-enantiomer in the presence of human kidney homogenate, BRL 42715 proved particularly stable, with 68% surviving after I hour s exposure to human kidney [90,91], In addition, BRL 42715 was only moderately bound (68%) to human serum. 

Thienamycin and its derivatives are exciting new antibiotics. Then-clinical use is limited, however, by their susceptibility to the kidney enzyme dehydropeptidase I. Reversible inhibition of this enzyme is provided by cilastatin [11]. The preparation of the S-cyclopropane portion [10] of cilastatin is achieved (16) by decomposition of ethyl diazoacetate in isobutylene [9] in the presence of the chiral copper catalyst R-7644. The product [10] is obtained in 92% e.e. and then further processed to cilastatin. Cilastatin is now marketed in combination with the thienamycin derivative imipenem as a very-broad-spectnim antibiotic. 

S)-2,2-dimethylcydopropane carboxamide is an intermediate for the production of the Merck dehydropeptidase inhibitor Cilastatin, which is administered with pe-nem and carbapenem antibiotics to prevent their degradation in the kidney [18]. Chemical and biotechnological processes were developed in parallel, but the bioprocess was simpler and resulted in a higher quality product. 

Some cyclopropanes have proved to be useful as pharmaceutical intermediates. The compound, (-i-)-S-2,2-dimethylcyclopropanecarboxyHc acid, is a component of cilastatin (Fig. 3), which is administrated in combination with imi-penem, a carbapenem antibiotic [7]. In spite of its high and wide antibacterial activity, imipenem is found to be easily decomposed in the kidneys. This metabolism is suppressed by cilastatin, an enzyme inhibitor for dehydropeptidase I. 

In 1984, Merck launched imipenem (N-formimidoylthienamycin). Imipenem acts as a nephrotoxin by interaction with the renal dehydropeptidase-1 (an enzyme of the kidney, which cleaves dipeptides and metabolises imipenem). For this reason, imipenem must be administered together with cilastatin [54, 55], which blocks dehydropeptidase-1. 

In 1985, the self-inactivating property of thienamycin was overcome by the use of a terminal imino functionality which is less nudeophilic. Imipenem (Fig. 22.32) has a broad spectrum of activity and is administered by deep intramuscular injection or as an intravenous infusion. Renal dehydropeptidase 1, an enzyme present in the kidney, attacks and inactivates imipenem. This problem has been overcome by the co-administration of imipenem with cilastatin, a renal dehydropeptidase 1 inhibitor. Mer-openem (Fig. 22.32), an analogue introduced in 1996, is stable to the action of renal dehydropeptidase 1 and is also administered by deep intramuscular injection or as an intravenous infusion. Since the discovery of thienamycin in 1976, only parenteral analogues have heen successfully used clinically because the carhapenem structure is unstable in both the stomach and intestine. 

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