Vol.53 No.S-1 July 2005
Stability of doripenem against human renal dehydropeptidase-I
Discovery Research Laboratories, Shionogi & Co., Ltd.,
3-1-1 Futaba-cho, Toyonaka, Osaka, Japan
Abstract
We evaluated the stability of doripenem, a novel carbapenem antibiotic, against human renal dehydropeptidase-I (DHP-I). Because imipenem, a carbapenem antibiotic, was reported to be easily hydrolyzed by human DHP-I, it is used in the clinic combined with DHP-I inhibitor cilastatin, so stability against human DHP-I plays an important roles in the human pharmacokinetics of carbapenem antibiotics.
We evaluated stability against DHP-I using recombinant human renal DHP-I, purified by cilastatin-coupled affinity chromatography from COS-1 cells producing DHP-I. Purified DHP-I was shown to form a broad single band in SDS-polyacrylamide gel electrophoresis, suggesting that it was produced as a glycosylated protein in COS-1 cells.
Stability was observed by determining the residual activity of the carbapenem antibiotics after incubation for 90 min in the presence of purified DHP-I. The residual activity of imipenem decreased with increasing activity of purified DHP-I. The residual activity of imipenem and meropenem after incubation with purified DHP-I was 20% and 80%, suggesting that meropenem, which is used without a DHP-I inhibitor in the clinic, is highly stable against DHP-I. Doripenem was as stable as meropenem under the same conditions, suggesting that doripenem and meropenem could be used without a DHP-I inhibitor in the clinic.
Key word
doripenem, dehydropeptidase-I
Received
January 24, 2005
Accepted
March 18, 2005
Jpn. J. Chemother. 53 (S-1): 92-95, 2005
