Biomedical subjects

D P Benziger

Publications and source records attributed to D P Benziger.

25 records · Page 2Linked to original sources

PubMed1980

Disposition of a series of tetrahydrocarbazoles.

Cyclindole was extensively metabolized and eliminated primarily via the kidneys from most laboratory animals and man. Only in the dog was cyclindole a major urinary component. Cyclindole was metabolized by N-demethylation and/or hydroxylation. In studies utilizing radiolabeled drug, the primary urinary component was polar material which probably resulted from conjugation of the hydroxylated products. When desmethylcyclindole was administered to rats and dogs, large amounts of unchanged drug were administered to rats and dogs, large amounts of unchanged drug were recovered in the urine; there was no 3-aminotetrahydrocarbazole present. Significant amounts of urinary radioactivity were thought to represent hydroxylated and/or conjugated products. When 7-hydroxycyclindole was administered to dogs, only free parent drug was recovered from the urine; there was no evidence for N-demethylation. Flucindole, the 6,8-difluoro analog of cyclindole was metabolized by dog and man via N-demethylation with the formyl derivative being a probable intermediate in this reaction; both products were found in the urine. No didesmethyl metabolite was detected. In contrast to cyclindole, the N-oxide of flucindole was found in urine from both species. The route of elimination of oxarbazole and its metabolites was species specific: urinary excretion was 96.5, 38.7, 24.5, and 2.0% for the guinea pig, monkey, rat, and dog, respectively. The major urinary metabolite was O-demethyl oxarbazole; this metabolite was conjugated in all species except the guinea pig. The dog and monkey excreted small quantities of conjugated N-debenzoylated oxarbazole in urine. The profound changes in pharmacological activity that result from relatively small chemical modifications of the tetrahydrocarbazole nucleus make it likely that many further investigations of this class of compounds will be undertaken in the future.

Animals↗

PubMed1979

Blood levels, tissue distribution and the duration of action in rats of ciprofibrate, a new hypolipidemic agent.

The blood levels, distribution and duration of action of ciprofibrate, an orally active hypolipidemic agent, was investigated in rats. Serum concentrations of 30 micrograms of ciprofibrate/ml are associated with significant reductions in both serum cholesterol and triglycerides in rats on a hyperlipidemic diet. Increasing the plasma concentrations of ciprofibrate to 69 micrograms/ml resulted in only a modest incremental reduction in serum lipids. The distribution of radioactivity from [14C]ciprofibrate within rat tissues was not affected by prior treatment for 14 days with ciprofibrate at either 1.5 or 3.0 mg/kg/day. Varying the dosage regimen of ciprofibrate at 30 mg/kg, with medication at intervals of one, 2 or 3 days resulted in similar peak plasma levels of about 300 micrograms/ml, 4 h after medication. The half-life of ciprofibrate, during the terminal disposition phase, was about 82 h. Levels of serum cholesterol remained suppressed up to 3 days after medication with ciprofibrate was discontinued; triglyceride levels returned to control values more slowly.

Animals↗

PubMed1978

Absorption and disposition of N-(1, 1-dimethylethyl)-N'-[2-(4-pyridinyl)-4-pyrimidinyl]urea in rats and dogs.

N-(1, 1-Dimethylethyl)-N'-[2-(4-pyridinyl)-4-pyrimidinyl]urea, Win 40, 882, was eliminated from the blood stream of dogs by two apparent first-order processes with alpha- and beta-phase half-lives of 0.2 hr and 1.4 hr, respectively. Radioactivity of the administered dose was excreted by rats in the feces and via the kidneys; about 40-45% of the dose was recovered in the feces, with the remainder in the urine, over a six day period. One of the terminal methyl groups of the tert-butyl moiety of Win 40,882 is sequentially oxidized by the rat to the alcohol, aldehyde and carboxylic acid. In addition, some of the aldehyde was further metabolized to generate two different monohydroxylated aldehydic metabolites; these hydroxyaldehydes accounted for less than 10% of the dose administered. An unusual metabolic pattern was noted in the excretion of Win 40,882. Over 30% of the urinary metabolites contained the carboxaldehyde function; only8% of the urinary radioactivity was represented by the further oxidation of the aldehyde group to generate the carboxylic acid.

Absorption↗

PubMedDate not supplied

Absorption, excretion and disposition of cyclindole in laboratory animals and human volunteers.

Radioactivity from orally administered single doses of cyclindole-14C was excreted primarily in the urine of the rat (99%/48 hr), monkey (80%/120 hr), and dog (70%/144 hr). Approximately 38-58% of a daily dose of cyclindole was recovered from 24-hr human urine, as determined by gas chromatography. Substantial amounts of unchanged drug were voided by dogs. Cyclindole was metabolized primarily by N-demethylation and/or hydroxylation in the 7-position. Hydroxylation at the 6-carbon atom was of minor importance in humans only; none of the animal species excreted the 6-hydroxy metabolite. Dogs were capable of N-demethylation, but no metabolites oxidized at the 6- or 7-carbon atoms were detected in dog urine.

Animals↗

PubMedDate not supplied

Metabolism of arildone, an antiviral agent, in laboratory animals.

After arildone administration, four compounds were identified in the excreta of laboratory animals: unchanged drug, arildone; the O-desmethyl metabolite, 4-[6-(2-chloro-4-hydroxy)phenoxy]hexyl-3,5-heptanedione; the sulfate ester of 2-chloro-4-methoxyphenol; and a labile conjugate of chlorohydroquinone, tentatively characterized as the sulfate ester. The concentrations of each of these were determined in the urine and/or plasma of rats, dogs, and mice after administration of 14C-arildone.

Animals↗

PubMedDate not supplied

Metabolism and disposition of sulfinalol in laboratory animals.

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.

Animals↗

PubMedDate not supplied

Metabolism of amrinone in animals.

The biotransformation of 14C-amrinone was studied in rats, dogs, and monkeys by automated gradient high-performance liquid chromatography. The major pathways of metabolism elucidated are: A) glucuronidation at the primary amino nitrogen atom and/or the enolized oxygen atom of the pyridone ring; B) addition of glutathione at the pyridone 2-position and ultimate hydrolysis of this compound to the 2-S-cysteinyl metabolite; C) formation of the primary amino N-acetyl derivative and subsequent oxidation of this to the corresponding N-glycolate. In each species studied, urine was the primary route of elimination and unchanged amrinone was the major urinary excretion product, the other known pathways being: rat, A and C; dog, A and B; monkey, A.

Administration, Oral↗