Effects of cilastatin on the pharmacokinetics of a new carbapenem, DA-1131, in rats, rabbits, and dogs

DA-1131, a new carbapenem antibiotic, undergoes renal metabolism by renal d ehydropeptidase I (DHP-I), located on the brush border of the proximal tubu lar cell. Species differences with regard to the effects of cilastatin, a r enal DHP-I inhibitor, were investigated after a 1-min intravenous infusion of DA-1131, with or without cilastatin, to rats, rabbits, and dogs. After i ntravenous infusion, the nonrenal clearance (CLNR) of DA-1131 was significa ntly slower in rats (3.00 versus 8.01 ml/min/kg) and rabbits (2.41 versus 6 .77 ml/min/kg) when the drug was coadministered with cilastatin; this could be due to the slower metabolism of DA-1131 by rat and rabbit kidney DHP-I. This indicated that renal metabolism of DA-1131 by renal DHP-I was inhibit ed by cilastatin. However, coadministration with cilastatin to dogs did not affect the CLNR of DA-1131.