Radioactivity was excreted in the urine and feces of rats, mice, and humans after a dose of 14C-cyproheptadine. The major metabolite in rat urine was unconjugated, but the majority of radioactive materials in mouse and human urine were conjugated with glucuronic acid. Identification of the rat urinary metabolite of cyproheptadine as an epoxide was accomplished with mass spectrometry and other methods. The rat metabolite was 10.11 -epoxydesmethylcyproheptadine and accounted for about 25% of a 45-mg dose of cyproheptadine per kg. Only a small amount of this epoxide was found in mouse urine, and none was apparent in the urine of two humans who received 5 mg of the drug. Dihydrodiols, which could arise by epoxide hydrase hydrolysis of possible 10.11-epoxy metabolites, were not found in the urine of any of the species studied. The spoxide found in rat urine appears to be unusually stable to in vivo hydrolysis. Possible implications of these results in the species-selective pancreotoxicity of cyproheptadine in the rat are presented.

Adult↗

PubMedDate not supplied

Studies on the fate of the glutathione and cysteine conjugates of acetaminophen in mice.

Studies were conducted in mice to examine the origin and fate of the amino acid-containing conjugates of acetaminophen (APAP). Collection of bile containing [14C]APAP metabolites (mainly the glutathione conjugate) in common duct-cannulated mice given a 250 mg/kg oral dose of the drug reduced by greater than 70% the urinary excretion of the cysteine and mercapturic acid conjugates of APAP. This confirmed previous reports which indicated that these urinary metabolites originated from the glutathione conjugate excreted in bile. The urinary excretion of cysteine and mercapturic acid conjugates was not altered, however, by ligation of the common bile duct in mice given APAP. Thus, biliary excretion of the glutathione conjugate is not obligatory for the appearance of cysteine and mercapturic acid conjugates in urine. Intravenous administration of purified glutathione conjugate to mice having a bile-duct cannula indicated that this conjugate did not appear in bile but appeared in urine primarily in the form of the cysteine conjugate. An identical pattern of excretion was observed after an iv dose of the purified cysteine conjugate of APAP to bile duct-cannulated mice. These results indicated that, if the glutathione conjugate leaves the liver via the blood, it is rapidly converted to the cysteine conjugate which is eliminated in urine. This conversion takes place at multiple sites in the body and evidence is presented to implicate both intestine and kidney in the process. The appearance of a small amount of glutathione conjugate in urine (16%) after an iv dose of the cysteine conjugate indicates that formation of the glutathione of APAP can occur by a route that does not involve direct conjugation of reactive metabolites of the drug with glutathione.

Acetaminophen↗

PubMedDate not supplied

Metabolism and disposition of the dopaminergic agonist 5-hydroxy-6-methyl-2-di-n-propylaminotetralin in the rat.

As part of a program to investigate the metabolism and disposition of putative dopamine receptor agonists, DK-118 (5-hydroxy-6-methyl-2-di-n-propylaminotetralin) was chosen for study in the rat. Following a 3.85 mg/kg (ip) dose of 5-hydroxy[6-14C]methyl-2-di-n-propylaminotetralin, an average (+/- SD) of 100.3 +/- 12.2% was recovered in 67 hr: 77.2 +/- 7.9% in urine and 23.1 +/- 6.2% in feces. No excretion of 14CO2 was observed. In bile duct-cannulated animals, an average of 31.6% of the dose was recovered in the bile within 6 hr. After injection of bile containing radiolabeled drug/metabolites into the lumen of the duodenum, 30.2 +/- 1.7% of the injected radioactivity was recovered in the urine, suggesting enterohepatic circulation of some of the drug/metabolites excreted in bile. Highest concentrations of tissue radioactivity, 0.5 hr after ip injection of 14C-DK-118, were found in lung, kidney, and liver. Only a small amount of unchanged DK-118 is excreted into urine and bile; HPLC radiochromatography separated five metabolites in urine and at least eight metabolites in bile. The three major metabolites in urine (70% of urinary radioactivity) have been identified as 5-hydroxy-6-carboxy-2-di-n-propylaminotetralin, 5-hydroxy-6-carboxy-2-n-propylaminotetralin, and 5-hydroxy-6-methyl-2-n-propylaminotetralin-O-sulfate. The two major biliary metabolites have been identified as 5-hydroxy-6-carboxy-2-n-propylaminotetralin and an acid-labile conjugate of DK-118. Together, these data indicate that DK-118 is metabolized in the rat by a combination of N-dealkylation, oxidation of the 6-methyl carbon, and conjugation with sulfate.

Animals↗

PubMedDate not supplied

Oxygen-18 incorporation studies of the metabolism of phenytoin to the catechol.

Phenytoin (PHT) is metabolized primarily to 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-HPPH), a 3,4-dihydrodiol metabolite (DHD), and a catechol, 5-(3,4-dihydroxyphenyl)-5-phenylhydantoin (Cat). The objective of the present studies was to determine the mechanism of Cat formation. The experiments were conducted with isolated rat hepatocytes and the 9000g supernatant fraction of mouse liver. Incubations of PHT were done under an 18O2 atmosphere and the incorporation of 18O into 4-HPPH and Cat was determined by mass spectrometry. It was found that the amount of Cat formed relative to the amount of 4-HPPH and DHD formed varied among the enzyme sources employed. However, in all cases, most of Cat formed from PHT contained two atoms of 18O. These results show that PHT is converted to Cat primarily by hydroxylation of 4-HPPH rather than by oxidation of DHD. Cat formation via DHD would add an 16O atom from hydrolysis of a 3,4-epoxide. Only 14-36% of the Cat formed contained one atom of 18O and one atom of 16O. Kinetic studies of Cat formation from 4-HPPH and DHD with rat liver subcellular fractions showed that the Vmax is higher and the Km is an order of magnitude lower with 4-HPPH than with DHD. These data suggest that DHD is only slowly converted to Cat and provide an explanation for the paucity of Cat formation via DHD when PHT is incubated with intact cells.

Animals↗

PubMedDate not supplied

Metabolism and disposition of cyproheptadine and desmethylcyproheptadine in pregnant and fetal rats.

The tissue distribution of unchanged drug and metabolites in pregnant rats was studied following oral administration of cyproheptadine (CPH) or its N-demethylated metabolite, desmethylcyproheptadine (DMCPH). A high performance liquid chromatographic (HPLC) method was developed for analysis of CPH and its metabolites in maternal and fetal tissues. In pregnant rats given CPH (11 mg/kg) during the final 2 or 8 days of gestation, the unchanged drug, DMCPH and desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) were detected in various maternal and fetal tissues, including pancreas, liver, lung, kidney and placenta. DMCPH and DMCPH-epoxide were also present in fetal tissues after 8 oral doses of DMCPH (11 mg/kg) to pregnant rats. Tissue concentrations of unchanged CPH and its metabolites, after each treatment regimen, were highest in the lung. Except for pancreas and brain, the levels of CPH, DMCPH, or DMCPH-epoxide in tissues at early times after completing CPH treatment were 3- to 10-fold higher in the dam than in the fetus. Brain levels of CPH metabolites were higher in the fetus than in the maternal animal. The metabolite DMCPH-epoxide appeared in fetal pancreas in concentrations equal to those in the maternal pancreas. In separate experiments designed to examine the metabolic capability of the fetus (day 20 of gestation), it was found that fetally administered CPH was not demethylated and, instead, epoxidated to form cyproheptadine-10,11-epoxide (CPH-epoxide). Administration of the metabolite DMCPH to the fetus showed that it was also readily converted to an epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗