Disposition of loratadine in healthy volunteers.

The absorption, metabolism and excretion of carbon-14-labeled loratadine (LOR, SCH 29851, Claritin) administered orally to healthy male volunteers were evaluated. Following a single oral 10-mg dose of [(14)C]LOR ( approximately 102 microCi), concentrations of LOR and desloratadine (DL; a pharmacologically active descarboethoxy metabolite of LOR) were determined in plasma. Metabolites in plasma, urine and feces were characterized using a liquid chromatography-mass spectrometry system (LC-MS) connected in line with a flow scintillation analyzer (FSA). Maximum plasma LOR and DL concentrations were achieved at 1.5 h and 1.6 h, respectively; thus, LOR was rapidly absorbed but also rapidly metabolized as indicated by these similar t(max) values. Metabolite profiles of plasma showed that LOR was extensively metabolized via descarboethoxylation, oxidation and glucuronidation. Major circulating metabolites included 3-hydroxy-desloratadine glucuonide (3-OH-DL-Glu), dihydroxy-DL-glucuronides, and several metabolites resulting from descarboethoxylation and oxidation of the piperidine ring. LOR was completely metabolized by 6 h post-dose. LOR-derived radiocarbon was excreted almost equally in the urine (41%) and feces (43%). About 13% of the dose was eliminated in the urine as 3-OH-DL-Glu. DL accounted for less than 2% of the dose recovered in the urine and only trace amounts of LOR were detected. 3-OH-DL was the major fecal metabolite ( approximately 17% of the dose). The combined amount of 5- and 6-hydroxy-DL contributed to an additional 10.7% of the dose in feces. Approximately 5.4% and 2.7% of the dose were excreted in the feces as unchanged drug and DL, respectively.

Disposition of desloratadine in healthy volunteers.

The absorption, metabolism and excretion of desloratadine (DL, Clarinex) were characterized in six healthy male volunteers. Subjects received a single oral 10-mg dose of [(14)C]DL ( approximately 104 microCi). Blood, urine and feces were collected over 240 h. DL was well absorbed; drug-derived radioactivity was excreted in both urine (41%) and feces (47%). With the exception of a single subject, DL was extensively metabolized; the major biotransformation pathway consisted of hydroxylation at the 3 position of the pyridine ring and subsequent glucuronidation (3-OH-DL-glucuronide or M13). In five of the six subjects, DL was slowly eliminated (mean t((1/2)) = 19.5 h) and persisted in the plasma for 48-120 h post-dose. This is in contrast to a t((1/2)) of approximately 110 h and quantifiable plasma DL concentrations for the entire 240-h sampling period in one subject, who was identified phenotypically as a poor metabolizer of DL. This subject also exhibited correspondingly lower amounts of M13 in urine and 3-OH-DL (M40) in feces. Disposition of DL in this subject was characterized by slow absorption, slow metabolism and prolonged elimination. Further clinical studies confirmed the lack of safety issues associated with polymorphism of DL metabolism (Prenner et al. 2006, Expert Opinion on Drug Safety, 5: 211-223).

Metabolism and excretion of loratadine in male and female mice, rats and monkeys.

The metabolism and excretion of loratadine (LOR), a long-acting non-sedating antihistamine, have been evaluated in male and female mice, rats and monkeys. Following a single (8 mg kg-1) oral administration of [14C]LOR, radioactivity was predominantly eliminated in the faeces. Profiling and characterization of metabolites in plasma, bile, urine and faeces from male and female mice, rats and monkeys showed LOR to be extensively metabolized with quantitative species and gender differences in the observed metabolites. In all species investigated, the primary biotransformation of LOR involved decarboethoxylation to form desloratadine (DL), subsequent oxidation (hydroxylation and N-oxidation) and glucuronidation. More than 50 metabolites were profiled using liquid chromatography-mass spectrometry (LC-MS) with in-line flow scintillation analysis (FSA) and characterized using LC-MSn techniques. The major circulating metabolite in male rats is a DL derivative in which the piperidine ring was aromatized and oxidized to pyridine-N-oxide. Much lower levels of the pyridine-N-oxide metabolite were observed in female rat plasma. In contrast, the relative amount of DL was notably higher in female than in male rats. The major circulating metabolite in either gender of mouse and male monkey is a glucuronide conjugate of an aliphatic hydroxylated LOR; in the female monkey, the major circulating metabolite is formed through oxidation of the pyridine moiety and subsequent glucuronidation. Qualitatively similar metabolic profiles were observed in the mouse, rat and monkey urine and bile, and the metabolites characterized resulted from biotransformation of LOR to DL, hydroxylation of DL and subsequent glucuronide conjugation. 5-Hydroxy-desloratadine was the major faecal metabolite across all three species irrespective of gender.

Sulfoxide-containing aromatic nitrogen mustards as hypoxia-directed bioreductive cytotoxins.

A series of diaryl and alkylaryl sulfoxide-containing nitrogen mustards were synthesized and evaluated for their hypoxia-selective cytotoxicity against V-79 cells in vitro as well as for their metabolism profiles with the rat S-9 fractions. In general, the diaryl sulfoxides (4, 5, and 7-9) showed much greater hypoxia selectivity (11-27-fold) than the alkylaryl sulfoxides (approximately 3-fold) (1 and 3). The fused diphenyl sulfoxides (10 and 11), on the other hand, showed very low hypoxia selectivity (1.3-3-fold). Compound 10 was highly cytotoxic under both aerobic and anaerobic conditions, while 11 showed low cytotoxicity under both conditions. The bioreduction of 8 by the rat S-9 fraction under anaerobic conditions was inhibited by menadione and enhanced by benzaldehyde, acetaldehyde, or 2-hydroxypyrimidine suggesting the involvement of aldehyde oxidase in the reduction of the sulfoxides. Bioreductive metabolism studies of selected model sulfoxides suggested that diaryl sulfoxides are better substrates for aldehyde oxidase than alkylaryl sulfoxides.