Metabolism, excretion, and pharmacokinetics of [14C] tigecycline, a first-in-class glycylcycline antibiotic, after intravenous infusion to healthy male subjects

被引:77
作者
Hoffmann, Matthew
DeMaio, William
Jordan, Ronald A.
Talaat, Rasmy
Harper, Dawn
Speth, John
Scatina, JoAnn
机构
[1] Wyeth Ayerst Res, Dept Biotransformat, Collegeville, PA 19426 USA
[2] Wyeth Ayerst Res, Dept Clin Res, Collegeville, PA 19426 USA
[3] Wyeth Ayerst Res, Dept Clin Pharmacol, Collegeville, PA 19426 USA
关键词
D O I
10.1124/dmd.107.015735
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Tigecycline, a novel, first-in-class glycylcycline antibiotic, has been approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. The pharmacokinetics, metabolism, and excretion of [C-14] tigecycline were examined in healthy male volunteers. Tigecycline has been shown to bind to bone; thus, to minimize the amount of radioactivity binding to bone and to maximize the recovery of radioactivity, tigecycline was administered intravenously (30-min infusion) as a single 100-mg dose, followed by six 50-mg doses, every 12 h, with the last dose being [ 14C] tigecycline (50 mu Ci). After the final dose, the pharmacokinetics of tigecycline in serum showed a long half-life (55.8 h) and a large volume of distribution (21.0 l/kg), whereas radioactivity in serum had a shorter half-life (6.9 h) and a smaller volume of distribution (3.3 l/kg). The major route of elimination was feces, containing 59% of the radioactive dose, whereas urine contained 32%. Unchanged tigecycline was the predominant drugrelated compound in serum, urine, and feces. The major metabolic pathways identified were glucuronidation of tigecycline and amide hydrolysis followed by N-acetylation to form N-acetyl-9-aminominocycline. The glucuronide metabolites accounted for 5 to 20% of serum radioactivity, and approximately 9% of the dose was excreted as glucuronide conjugates within 48 h. Concentrations of N-acetyl-9-aminominocycline were approximately 6.5% and 11% of the tigecycline concentrations in serum and urine, respectively. Excretion of unchanged tigecycline into feces was the primary route of elimination, and the secondary elimination pathways were renal excretion of unchanged drug and metabolism to glucuronide conjugates and N-acetyl-9-aminominocycline.
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页码:1543 / 1553
页数:11
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