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

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Abstract
The effects of 2 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 .apprx. 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 .gtoreq. 1:0.25, the urinary recovery was .apprx. 72% in all subjects; it varied between 7.7-43% 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 latter part of the 10 h observation period after each administration. At a 1:1 ratio of the 2 drugs, the inhibition of renal metabolism of N-formimidoyl thienamycin was maintained for at least 8 h, renal clearance declined as soon as 4 h after administration of a 1:0.25 ratio. Thus, MK-789 and MK-791 alter the renal excretion of N-formimidoyl thienamycin from glomerular filtration plus tubular secretion to glomerular filtration only, possibly competitively inhibiting the penetration of N-formimidoyl thienamycin into the proximal tubular cells.