Norrby S R, Alestig K, Björnegård B, Burman L A, Ferber F, Huber J L, Jones K H, Kahan F M, Kahan J S, Kropp H, Meisinger M A, Sundelof J G
Antimicrob Agents Chemother. 1983 Feb;23(2):300-7. doi: 10.1128/AAC.23.2.300.
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.
N-甲脒基硫霉素（MK0787）通过位于近端肾小管细胞刷状缘的二肽酶——脱氢肽酶I进行肾脏代谢。在41名接受N-甲脒基硫霉素与MK-789或MK-791不同组合的健康受试者中，研究了脱氢肽酶I的两种抑制剂（MK-789和MK-791）对N-甲脒基硫霉素药代动力学的影响。两种抑制剂对N-甲脒基硫霉素的血浆动力学影响都很小。血浆浓度和血浆浓度曲线下面积增加约20%，血浆清除率相应降低。血浆半衰期无显著改变。同时给予MK-789或MK-791导致N-甲脒基硫霉素的尿回收率和肾脏清除率均匀且显著增加。因此，在N-甲脒基硫霉素/MK-791比例为1:0.25或更高时，所有受试者的尿回收率约为72%，而单独给予N-甲脒基硫霉素时，尿回收率在7.7%至43%之间变化。N-甲脒基硫霉素与MK-791的剂量比影响反应。在相对较高剂量的MK-791时，每次给药后10小时观察期的后期，N-甲脒基硫霉素的尿回收率、肾脏清除率和尿浓度显著增加。在两种药物比例为1:1时，对N-甲脒基硫霉素肾脏代谢的抑制作用维持至少8小时，而在给予1:0.25比例药物后4小时，肾脏清除率就开始下降。结果表明，MK-789和MK-791可能通过竞争性抑制N-甲脒基硫霉素进入近端肾小管细胞，将N-甲脒基硫霉素的肾脏排泄从肾小球滤过加肾小管分泌改变为仅肾小球滤过。
