title: Metabolism, excretion, and pharmacokinetics of [14C]tigecycline, a first-in-class glycylcycline antibiotic, after intravenous infusion to healthy male subjects.
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 microCi). 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 drug-related 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.
authors.affiliation: Department of Biotransformation, Wyeth Research, 500 Arcola Road/S3226, Collegeville, PA 19426, USA. hoffmam7@wyeth.com
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: William
authors.initials: W
authors.lastname: DeMaio
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Jordan
authors.forename: Rasmy
authors.initials: R
authors.lastname: Talaat
authors.forename: Dawn
authors.initials: D
authors.lastname: Harper
authors.forename: John
authors.initials: J
authors.lastname: Speth
authors.forename: JoAnn
authors.initials: J
authors.lastname: Scatina
mesh_terms: D000107:Acetylation; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008911:Minocycline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D020719:Glucuronides; D000078304:Tigecycline; D008911:Minocycline