Disposition of (5H-dibenzo [a,d]cyclohepten-5-ylidene)acetic acid in laboratory animals.

The disposition of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (Wy-41,770), an anti-inflammatory agent, was investigated in rats, mice, rhesus monkeys, and dogs following single 12.5-mg/kg doses of 14C-labeled or unlabeled drug and in rodents receiving single 225-mg/kg doses of 14C-Wy-41,770. The drug was rapidly and well absorbed in all four animal species. Following an iv dose, plasma elimination half-lives of Wy-41,770 in monkeys and dogs were, respectively, 5.0 +/- 1.8 and 0.24 +/- 0.01 hr. Total body clearances (CL) of 1.8 +/- 0.2 ml/min/kg in monkeys and 7.7 +/- 1.1 ml/min/kg in dogs are low, indicating that, after an ig dose, little Wy-41,770 would be eliminated on first passage through the liver. The steady state volumes of distribution of 0.37 +/- 0.1 and 0.14 +/- 0.01 liters/kg, respectively, in monkeys and dogs are low, indicating limited extravascular distribution of Wy-41,770. Plasma half-lives of Wy-41,770 in rats and mice were, respectively, 10.8 and 8.4 hr. The longer half-life in rats compared to other animals is due to the extensive enterohepatic recycling of the drug in rats. The extensive cycling of the drug in rats may explain why ileocecal inflammation occurred in this species but not in mice and dogs following prolonged oral administration of high doses of Wy-41,770. Following a 12.5 mg/kg, ig dose, the rates of urinary excretion of radioactivity in monkeys, mice, and rats were, respectively, 73.4 +/- 10.7, 52.6 and 15.2% of the dose, whereas the fecal excretion was 9.1 +/- 3.7% in monkeys and 74.7% in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent pharmacokinetics of the antihypertensive 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5-(6H)-one in dogs and rats.

A sensitive and reproducible GLC assay was developed for determining 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one (I) in biological fluids, utilizing the electron-capturing capability of the heptafluorobutyryl derivative. After single 2.5- and 10-mg/kg oral and intravenous doses to three dogs, plasma concentration-time data for I were fitted to a biexponential equation and pharmacokinetic parameters were calculated. A dose-dependency for certain parameters, most notably total body clearance (ClT), was indicated. The difference in ClT for the low and high dose was statistically significant. After single 5-, 25-, and 50-mg/kg intragastric doses were given to rats, the decline in plasma concentrations of I with time followed a monoexponential equation. As with dogs, there was a disproportionate change in kinetic parameters with increasing dose for rats. While simple Michaelis-Menten kinetics were not evident, nonlinearity in biotransformation (intrinsic clearance) appeared to be the cause for the dose-dependent pharmacokinetics.

Diastereoisomeric glucuronides of oxazepam. Isolation and stereoselective enzymic hydrolysis.

Oxazepam glucuronide isolated from swine urine by previously published methods was separated into its diastereoisomers by ion-exchange chromatography on a preparative scale. Quantitative high-performance liquid chromatography was used to monitor the separation. The two isomers were obtained in analytically pure form and then characterized by elemental analysis, oxazepam content, mass spectrometry, ultraviolet spectroscopy, optical rotation and optical rotatory dispersion-circular dichroism. The latter permitted the assignment of the dextrorotatory and the levorotatory isomers to the (S)- and (R)- configurations, respectively. Rates of enzymic hydrolysis depend on the configuration of the substrate as well as on the enzyme preparation used. Rate of cleavage was highest with the (S)-(+)-glucuronide and beta-glucuronidase from Escherichia coli. This enzyme possesses the highest degree of stereoselectivity; it hydrolyzes the (S)-(+)-isomer more than 400 times faster than the (R)-(-)-form. Bovine liver glucuronidase is less stereoselective, whereas glucuronidase preparations of molluscan origin exhibit little stereoselectivity. The ready hydrolysis of one of the glucuronides by an enzyme from an intestinal microorganism may play a role in the enterohepatic circulation of oxazepam.

Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam.

Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Lorazepam: glucuronide formation in the cat.

The excretion and metabolism of lorazepam was studied in domestic cats. After oral administration of 14-C-lorazepam (1 mg/kg), the mean percent of the dose excreted in urine was 47.3 plus or minus 6.7% (SD) and in feces 54.0 plus or minus 6.1% (SD). The main urinary metabolite was lorazepam glucuronide; its mean excretion over the first 3 days amounted to 29% of the dose (66% of urinary radioactivity). When 20 mg of unlabeled drug per kg was given, about 40% of the dose was excreted into urine as lorazepam glucuronide within 6 days. Conculsive evidence for the glucuronide structure was obtained by chemical analysis and mass spectrometry of the lorazepam conjugate isolated from cat urine. The radioactivity in urine which was not attributable to several minor metabolites. In plasma, both lorazepam and lorazepam glucuronide were present. These findings indicate that the cat is capable of using glucuronidation as a major route of conjugation, contrary to the many reports that cats conjugate exogenous materials poorly with glucuronic acid.