An overview of the pharmacology of imipenem/cilastatin

Imipenem is the first clinically available carbapenem antibiotic. Since it is hydrolysed by dehydropeptidase-I, a zinc metallo-enzyme resident in the brush border of the renal tubule, it is co-administered with cilastatin, a reversible inhibitor of this enzyme. This provides clinically relevant concentrations of imipenem in the urine for 8-10 h after a 500 mg dose. The half-life of both drugs is 1 h in normal volunteers. Plasma clearances are reproducible between volunteers and studies and average 220 ml/min for imipenem. Renal clearance of unchanged imipenem accounts for 60-70% of plasma clearance when the imipenem is given with cilastatin. Administration of radiolabelled drugs results in recovery of over 99% of the radiolabel in the urine for both imipenem and cilastatin. With increasing renal dysfunction, the half-life of imipenem is controlled by a metabolic clearance pathway which is unaffected by cilastatin. Renal clearance is by glomerular filtration and active tubular secretion for both imipenem and cilastatin. Renal dysfunction results in terminal half-lives of slightly greater than 4 h for imipenem and 16 h for cilastatin in the functionally anephric. Both drugs are well cleared by haemodialysis and supplemental 500 mg doses are recommended after a dialysis. In the case of severe renal failure, dose and schedule alterations serve to prevent accumulation of cilastatin and circulating metabolites of imipenem, while still providing therapeutic concentrations of imipenem.