Urinary Recovery of N -Formimidoyl Thienamycin (MK0787) as Affected by Coadministration of N -Formimidoyl Thienamycin Dehydropeptidase Inhibitors

Abstract

N -Formimidoyl thienamycin (MK0787) undergoes renal metabolism by a dipeptidase, dehydropeptidase I, located on the brush border of the proximal tubular cells. The effects of two inhibitors (MK-789 and MK-791) of dehydropeptidase I on the pharmacokinetics of N -formimidoyl thienamycin were studied in 41 healthy subjects receiving various combinations of N -formimidoyl thienamycin and MK-789 or MK-791. Both inhibitors affected the plasma kinetics of N -formimidoyl thienamycin only to a small extent. Plasma concentrations and the area under the plasma concentration curve increased about 20% with a proportional decrease in plasma clearance. Plasma half-life was not altered significantly. Coadministration of MK-789 or MK-791 resulted in uniform and marked increases in urinary recovery and renal clearance of N -formimidoyl thienamycin. Thus, at an N -formimidoyl thienamycin/MK-791 ratio of 1:0.25 or higher, the urinary recovery was about 72% in all subjects, whereas it varied between 7.7 and 43% when N -formimidoyl thienamycin was given alone. The ratio of the N -formimidoyl thienamycin and MK-791 doses affected response. At relatively higher doses of MK-791, significant increases of N -formimidoyl thienamycin urinary recovery, renal clearance, and urine concentrations occurred during the later part of the 10-h observation period after each administration. At a 1:1 ratio of the two drugs, the inhibition of renal metabolism of N -formimidoyl thienamycin was maintained for at least 8 h, whereas renal clearance declined as soon as 4 h after the administration of a 1:0.25 ratio. The results indicated that MK-789 and MK-791 alter the renal excretion of N -formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly by competitively inhibiting the penetration of N -formimidoyl thienamycin into the proximal tubular cells.