In a metabolism study, three male and three female pediatric dogs and three male and three female adult beagle dogs received a single oral dose of 60 mg/kg [14C]felbamate. Urine and feces were collected up to 72 hr. Excreta samples were extracted with ethyl acetate and 14C metabolite profiles were generated by HPLC analysis of the extracts. The total 14C dose recoveries were 88.2% for the pediatric and 85.9% for the adult groups; recovery in urine accounted for 61.7 and 69.7%, respectively. The 14C metabolite profiles in urine and feces were similar, with three major peaks corresponding to unchanged felbamate and two hydroxylated metabolites. There was no significant sex difference in profiles within each age group. However, the sum amount of all metabolites in the urine was higher, and the amount of unchanged drug was lower in pediatric dogs. For the 0-24 hr samples, the metabolites/drug ratio in urine was 2.0-2.1 for pediatric dogs and 1.0-1.2 for adult dogs. This indicated a higher metabolic rate in the pediatric dogs.

Administration, Oral↗

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Tissue distribution and lung localization of [14C]azelastine in guinea pigs.

Tissue distribution was performed in male guinea pigs that received a single oral dose of 1 mg/kg [14C]azelastine. Determination of 14C concentrations by liquid scintillation counting in 16 tissues and by whole-body autoradiography showed preferential uptake of the radioactivity by the lung. The liver had a higher and all other tissues had lower concentrations of 14C than the lung. The lowest 14C concentrations were in the eyes and brain. Light microscopy autoradiography of lung and trachea sections indicated localization of 14C, possibly in alveolar macrophages. The radioactivity cleared completely from lung tissue, as well as from other tissues within 48 hr.

Animals↗

PubMedDate not supplied

Metabolism of [14C]azelastine in guinea pigs.

A specific HPLC separation method was used to generate 14C metabolite profiles in lung, muscle, and liver tissue and in bile, urine, and feces obtained from male guinea pigs that received a single oral dose of 1 mg/kg [14C]azelastine. Profiles were also generated in urine and feces of animals that received a single iv dose of labeled drug. In lung and muscle tissue, azelastine (AZ) and desmethylazelastine (DAZ) were the major components of 14C radioactivity. The amount of the amino acid metabolites (2- and 7-ACID), formed by oxidation and azepinyl ring opening, was relatively small. In the liver significant amounts of the 7-ACID were observed in addition to AZ and DAZ. The major metabolite in bile, urine, and feces was the 7-ACID, with much less AZ and DAZ present. The balance of 14C in the form of AZ and three metabolites in excreta (percentage of dose) was: AZ, 9.7-10.5%; DAZ, 8.7-9.6%; 2-ACID, 2.9-3.0%; and 7-ACID, 43.0-54.6%. No large differences in the quantitative profile between the two dosing routes were observed.

Animals↗

PubMedDate not supplied

Felbamate pharmacokinetics in the rat, rabbit, and dog.

Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.

Administration, Oral↗

PubMedDate not supplied

Felbamate metabolism in the rat, rabbit, and dog.

Two major and one minor metabolite of felbamate (FBM) as well as unchanged drug were isolated and identified by electron impact and chemical ionization mass spectrometry from rat and dog urine after dosing with [14C]FBM. The metabolites were 2-(4-hydroxyphenyl)-1,3-propanediol dicarbamate (p-OHF), 2-hydroxy-2-phenyl-1,3-propanediol dicarbamate, and 2-phenyl-1,3-propanediol monocarbamate. The metabolites and FBM were excreted mainly in urine, where their sum accounted to 81-94% of the radioactivity in hydrolyzed rat urine samples, 71-82% in rabbit urine samples, and 69-83% in dog urine samples. The amount of metabolites in the conjugated form was estimated to be 20-35% in rat, 20-30% in rabbit, and 10-20% in dog urine. The major biliary metabolite in all three species was p-OHF, whereas the amount of FBM was small. Metabolites found in dog feces were the same as those in the urine.

Animals↗