Metabolism, Excretion, and Pharmacokinetics of [¹⁴C]Tigecycline, a First-In-Class Glycylcycline Antibiotic, after Intravenous Infusion to Healthy Male Subjects

Abstract

ABSTRACT: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 [ 14 C]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 [ 14 C]tigecycline (50 Ci). After the final dose, the pharmacokinetics of tigecycline in serum showed a long halflife (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.

Thermal Analysis and Validation of UV and Visible Spectrophotometric Methods for the Determination of New Antibiotic Tigecycline in Pharmaceutical Product

“…Chemically, tigecycline is [(4S, 4aS, 5aR, 12aS) -9-(2 -tert-Butylaminoacetylamino)-4,7-bis-dimethylamino-3,10,12,12a-tetrahy droxy−1,11-dioxo−1,4,4a,5,5a,6,11,12a-octahydronaph-tha cene-2-carboxamide]. Its chemical formula is C 29 H 39 N 5 O 8 , and its molecular weight is 585.65 Daltons [6,7].…”

“…Four HPLC-UV assays for the determination of tigecycline in biological materials have been described in the literature [6,[8][9][10][11]. Besides The literature has reported analytical methods for determination of antibiotics such as chromatography, spectroscopy, spectrophotometry and microbiological assay.…”

Determination of tigecycline in turkey plasma by LC-MS/MS: validation and application in a pharmacokinetic study

“…Chemically, TIG is (4S,4aS,5aR,12aS)-9-(2-tert-butylaminoacetylamino) -4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a- (Hoffmann et al 2007).…”

High serum concentrations of ciclosporin related to administration of tigecycline

“…It is primarily eliminated via bile (59%); renal excretion (33%) and glucuronidation are secondary ways of elimination. Its elimination half-life is approximately 40 h (37-67 h) [7,8].…”

“…It is primarily eliminated via bile (59%); renal excretion (33%) and glucuronidation are secondary ways of elimination. Its elimination half-life is approximately 40 h (37-67 h) [7,8].As a relatively new agent, little is known about interactions with other drugs. Potential mechanisms which may explain the pharmacological interaction in our case Eur…”