Pharmacokinetics and metabolism of UK-383,367 in rats and dogs: a rationale for long-lived plasma radioactivity.

UK-383,367 (5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl}-1,2,4-oxadiazole-3-carboxamide) is a novel procollagen C-proteinase inhibitor evaluated for the treatment of post-surgical dermal scarring. It is extensively metabolized in rat and dog absorption, distribution, metabolism and excretion studies, and a metabolic pathway for UK-383,367 was determined. A long-lived metabolite was identified in dog plasma. Data indicate that this metabolite results from the oxadiazole ring-cleavage-producing oxamic acid, oxamide and oxalic acid. Ion exclusion chromatography was used to identify these polar metabolites, which were unretained on a standard reversed-phase high-performance liquid chromatography system. The oxamide metabolite was identified as the long-lived radioactivity, which was observed in dog plasma.

A sensitive HPLC-MS-MS assay for quantitative determination of midazolam in dog plasma.

The clinical pharmacokinetics of midazolam have been extensively studied, due to its high clearance by CYP3A4 and sensitivity to drug-drug interactions. In order to investigate the potential to model drug-drug interactions with midazolam in the dog, a selective and sensitive high performance liquid chromatography-tandem mass spectroscopy (HPLC-MS-MS) method has been developed, with sufficient sensitivity to allow analysis of dog plasma samples generated following administration of a clinically relevant dose. The method involves extraction of midazolam and internal standard (flunitrazepam) from dog plasma, using 96-well Oasis MCX solid phase extraction plates. The assay has been validated over a concentration range of 0.1-10 ng/ml and its specificity, accuracy and precision demonstrated. The relative bias of the assay was within +/-15% for all standards with intra- and inter-assay precision (coefficient of variation-%CV) of less than 15%. The assay was applied to the analysis of plasma samples (0.2 ml), generated following intravenous or oral administration of midazolam to male beagle dogs, at a dose level of 0.05 mg/kg, and pharmacokinetic parameters were derived from the resulting data.

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.