Metabolism and disposition of the v-integrin ß3/ß5 receptor antagonist cilengitide, a cyclic polypeptide, in humans

被引:21
作者
Becker, Andreas [1 ]
von Richter, Oliver [1 ]
Kovar, Andreas [2 ]
Scheible, Holger [3 ]
van Lier, Jan J. [4 ]
Johne, Andreas [1 ]
机构
[1] Merck KGaA, Merck Serono Global Early Dev, Dept Clin Pharmacol, D-64293 Darmstadt, Germany
[2] Sanofi Aventis, Frankfurt, Germany
[3] Merck KGaA, Merck Serono Global Early Dev, Inst Drug Metab & Pharmacokinet, D-64293 Darmstadt, Germany
[4] PRA, Zuidlaren, Netherlands
关键词
cilengitide; mass balance; disposition; human; CYCLOSPORINE METABOLITES; P-GLYCOPROTEIN; SOLID TUMORS; HUMAN BILE; PHASE-I; PEPTIDES; ALPHA-V-BETA-3; EMD-121974; EXCRETION; PATHWAYS;
D O I
10.1002/jcph.482
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cilengitide (EMD 121974, manufactured by Merck KGaA, Darmstadt, Germany) is an v-integrin receptor antagonist showing high affinity for v3 and v5.This study determined the mass balance of cilengitide in healthy volunteers receiving a single intravenous infusion of 2.1 MBq C-14-cilengitide spiked into 250mL of 2000mg of cilengitide. Blood, urine, and feces were collected up to day 15 or until excretion of radioactivity was below 1% of the administered dose. Total radioactivity derived from the administration of C-14-cilengitide and unlabeled cilengitide levels were determined and used for calculation of pharmacokinetic parameters.C-14-cilengitide-related radioactivity was completely recovered (94.5%; 87.4%-100.6%) and was mainly excreted into urine (mean, 79.0%; range, 70.3%-88.2%) and to a lesser extent into feces (mean, 15.5%; range, 9.3%-20.3%). Of the administered dose, 77.5% was recovered as unchanged cilengitide in urine. The concentration profiles of cilengitide and total radioactivity in plasma were comparable. No circulating metabolites were identified in plasma and urine. Two metabolites,M606-1 and M606-2, were identified in feces considered to be formed by intestinal peptidases or by peptidases from fecal bacteria. In conclusion, the data show that following intravenous administration, C-14-cilengitide was completely recovered, was excreted mainly via renal elimination, and was not metabolized systemically.
引用
收藏
页码:815 / 824
页数:10
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