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.

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ABSTRACT:Vabicaserin is a potent 5-hydroxtryptamine 2C full agonist with therapeutic potential for a wide array of psychiatric disorders. Metabolite profiles indicated that vabicaserin was extensively metabolized via carbamoyl glucuronidation after oral administration in humans. In the present study, the differences in the extent of vabicaserin carbamoyl glucuronide (CG) formation in humans and in animals used for safety assessment were investigated. After oral dosing, the systemic exposure ratios of CG to vabicaserin were approximately 12 and up to 29 in monkeys and humans, respectively, and the ratios of CG to vabicaserin were approximately 1.5 and 1.7 in mice and dogs, respectively. These differences in systemic levels of CG are likely related to species differences in the rate and extent of CG formation and elimination. Whereas CG was the predominant circulating metabolite in humans and a major metabolite in mice, dogs, and monkeys, it was a relatively minor metabolite in rats, in which oxidative metabolism was the major metabolic pathway. Although the CG was not detected in plasma or urine of rats, approximately 5% of the dose was excreted in bile as CG in the 24-h collection postdose, indicating the rat had the metabolic capability of producing the CG. In vitro, in a CO 2 -enriched environment, the CG was the predominant metabolite in dog and human liver microsomes, a major metabolite in monkey and mice, and only a very minor metabolite in rats. Carbamoyl glucuronidation and hydroxylation had similar contributions to vabicaserin metabolism in mouse and monkey liver microsomes. However, only trace amounts of CG were formed in rat liver microsomes, and other metabolites were more prominent than the CG. In conclusion, significant differences in the extent of formation of the CG were observed among the various species examined. The exposure ratios of CG to vabicaserin were highest in humans, followed by monkeys, then mice and dogs, and lowest in rats, and the in vitro metabolite profiles generally correlated well with the in vivo metabolites.Vabicaserin is a potent 5-hydroxtryptamine 2C (5-HT 2C ) full agonist and shows in vitro functional selectivity for 5-HT 2C over 5-hydroxtryptamine 2A (5-HT 2A ) and 5-hydroxtryptamine 2B (5-HT 2B ) receptors . Vabicaserin is effective in several animal models that are predictive of antipsychotic activity, with an atypical antipsychotic profile (Marquis et al., 2006). Administration of vabicaserin decreases nucleus accumbens dopamine without affecting striatal dopamine, which indicates mesolimbic selectivity (Marquis et al., 2006;Wacker and Miller, 2008). This profile is consistent with potential efficacy in the treatment of the psychotic symptoms of schizophrenia with decreased liability for extrapyramidal side effects. In addition, long-term administration of vabicaserin significantly decreases the number of spontaneously active mesocorticolimbic dopamine neurons without affecting nigrostriatal dopamine neurons (Marquis et al., 2006), consistent with the effects of atypi...

Background: This series of experiments was conducted to describe the metabolic profile of the serotoninnorepinephrine reuptake inhibitor desvenlafaxine (administered as desvenlafaxine succinate) using animal and human models. Methods: In vivo and in vitro experiments were conducted with humans and preclinical species (CD-1 mice, Sprague Dawley rats, and beagle dogs). Single oral doses of [ 14 C]-desvenlafaxine were administered to each preclinical species for analyses of desvenlafaxine concentration in plasma, urine, and feces. Rats also were subjected to whole body autoradiography and quantitative tissue sampling. The major UDP-glucuronosyltransferase (UGT) isoforms involved in the formation of desvenlafaxine-O-glucuronide were also assessed. In vivo human experiments were conducted with healthy volunteers administered desvenlafaxine 100, 300, or 600 mg, followed by 72 hours of plasma sampling. In vitro experiments were conducted with human and animal liver microsomes and human hepatocytes to determine the effect of desvenlafaxine on cytochrome P450 (CYP) enzyme activity. Desvenlafaxine concentrations were measured using high performance liquid chromatography and liquid chromatography/mass spectrometry methods. Results: The primary metabolic pathways for desvenlafaxine included glucuronidation, oxidation, and N-demethylation. In humans, desvenlafaxine was the predominant drug-related species in plasma and urine. However, in mice, rats, and dogs, desvenlafaxine-O-glucuronide was the most commonly detected in plasma and urine. Urine was the primary route of excretion of desvenlafaxine in all species. Multiple UGTs were capable of desvenlafaxine metabolism. Oxidative metabolism via the CYP3A4 was a minor contributor to desvenlafaxine metabolism; however, desvenlafaxine did not induce or inhibit CYP3A4 activity. Desvenlafaxine did not act as a significant mechanism-based inhibitor of the assessed CYP isoenzymes. Conclusion: These findings support other study results suggesting that desvenlafaxine has a simple metabolic profile. Desvenlafaxine is unlikely to contribute to clinically significant CYP-mediated drug-drug interactions. The relatively simple metabolic profile of desvenlafaxine may lead to clinical benefits in those patients being treated for major depressive disorder.

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ABSTRACT:Vabicaserin is a potent 5-hydroxytryptamine 2C agonist that is currently being developed for the treatment of the psychotic symptoms of schizophrenia. In this study, in vitro and in vivo metabolism of vabicaserin was evaluated in mice, rats, dogs, monkeys, and humans, and the structures of the metabolites were characterized by liquid chromatography/mass spectrometry and NMR spectroscopy. Vabicaserin underwent three major metabolic pathways in vitro: NADPH-dependent hydroxylation, NADPH-independent imine formation, and carbamoyl glucuronidation. After a single oral dose, vabicaserin was extensively metabolized in animals and humans, and its metabolites were mainly excreted via the urine in mice and rats. Along with the metabolites observed in vitro, secondary metabolism via oxidation and conjugation of the primary metabolites generated from the abovementioned three pathways yielded a number of additional metabolites in vivo. Carbamoyl glucuronidation was the major metabolic pathway in humans but a minor pathway in rats. Although carbamoyl glucuronidation was a major metabolic pathway in mice, dogs, and monkeys, oxidative metabolism was also extensive in these species. Hydroxylation occurred in all species, although different regional selectivity was apparent. The imine pathway also appeared to be common to several species, because vabicaserin imine was observed in humans and hydroxyl imine metabolites were observed in mice, rats, and dogs. A nitrone metabolite of vabicaserin was observed in dogs and humans but not in other species. In conclusion, the major metabolic pathways for vabicaserin in humans and nonclinical safety species include carbamoyl glucuronidation, hydroxylation, formation of an imine, and a nitrone.

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