Since Gomez-Sanchez isolated 19-nor-DOC from the urine of rats with adrenal regeneration hypertension, we have demonstrated that 19-nor-DOC is a naturally occurring substance in other hypertensive animal models as well as in man. Certain 19-nor-corticosteroids are potent mineralocorticoids and may have a role in the regulation of systemic arterial blood pressure and could be involved in the pathogenesis of hypertension. We have previously demonstrated that 19-nor-DOC is greatly influenced by ACTH and dexamethasone but less so by high and low sodium diets in normotensive human subjects and, that 19-nor-DOC is greatly increased in some but not all hypertensive patients. Studies by Gomez-Sanchez and by our own group have shown that 19-nor-DOC is not secreted by the adrenal gland directly but rather the adrenal secretes a 19-oic-DOC precursor which is converted peripherally by extra-adrenal tissues. Biosynthesis of 19-oic-DOC has been demonstrated to occur by prior hydroxylation of DOC and progressive oxydation to the acidic form. More recently it has been shown that 19-nor-DOC is excreted in the urine of mammals as a free unconjugated compound but to a greater extent as a 21-monoglucuronide. In the studies described we will report the quantification of urinary excretion of 19-nor-DOC as a free and unconjugated compound and also as a 21-monoglucuronide in patients with hypertension as well as in patients with specific forms secondary hypertension such as that found in 17 alpha hydroxylase deficiency which is a syndrome associated with hypogonadism, hypertension and hypokalemia. In this disorder of cortisol biosynthesis adlosterone production, is not elevated and therefore other known and unknown mineralocorticoid account for the excess in mineralocorticoid activity observed. Our study demonstrated that 19-nor-DOC, the potent hypertensinogenic mineralocorticoid was elevated in both plasma and urine from a young woman with 17-alpha hydroxylase deficiency. This patient was examined for various corticosteroids in basal and ACTH-stimulated, dexamethasone-suppressed and cortisol-treated states. In the basal state, urinary and plasma 17 alpha-hydroxy corticosteroids were decreased but the 17-deoxycorticosteroids were extremely elevated including corticosterone, 18-hydroxy corticosterone, tetrahydro corticosterone, tetrahydro-deoxycorticosterone and 18 hydroxy-tetrahydro-DOC. Both basal urinary free 19-nor-DOC was markedly elevated both by HPLC and radioimmunoassay measurements.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗

PubMedDate not supplied

The biotransformation of (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy) acetic acid (MK-196) in the chimpanzee.

The metabolism of a novel polyvalent saluretic agent (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196) was studied in the chimpanzee. Following oral administration, 50% of the radioactive dose was recovered in the urine in four days; 8-14% of the dose was excreted as unchanged drug. The fecal specimens accounted for 5-9% of the dose. Following intravenous administration an initial rapid elimination of drug from the plasma was observed [(t1/2)alpha approximately 0.4 hr, (t1/2)beta approximately 4 hr]. The data are consistent with the rapid elimination of radioactivity, approximately 30% of dose, in the urine during the first 24 hr, followed by a much slower rate of excretion of drug and metabolites. These findings are congruous with the high affinity (greater than 98%) of MK-196 and the major metabolite with plasma proteins. The urinary metabolites were isolated and identified by the following techniques: solvent extraction, column, thin-layer, and gas-liquid chromatography, derivatization, and mass and nuclear magnetic resonance spectroscopy. The major metabolite, which resulted from para-hydroxylation of the 2-phenyl substitutent, accounted for about 40% of the urinary radioactivity. Reduction of the ketone group, methylation of the p-hydroxy group, and additional phenyl ring hydroxylation were also shown to occur. There was no evidence for glucuronide formation nor did SKF-525-A inhibit the metabolism of the drug in the chimpanzee. Under conditions of induced metabolic alkalosis, the urinary levels of MK-196 increased from 11 to 40%. Probenecid and p-aminohippurate administered during metabolic alkalosis decreased the clearance of drug (40 to 15%).

Administration, Oral↗

PubMedDate not supplied

Metabolism of a new HIV-1 reverse transcriptase inhibitor, 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (L-696,229), in rat and liver slices.

L-696,229 is a potent and specific inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and is currently undergoing clinical evaluation. In vivo metabolism in rats was investigated using an intravenous bolus dose of 5 mg/kg [3H]L-696,229. The amount of radioactivity eliminated in bile and urine over a period of 6 hr was 60 and 22%, respectively. Radiochromatographic analysis of the bile and urine showed that L-696,229 was metabolized rapidly and completely to several common metabolites. Sequential oxidation at the alpha-position of the 5-ethyl group to an acetyl moiety, aromatic hydroxylation of the benzoxazole group (position C4', C6', or C7'), and subsequent sulfate conjugation were the major metabolic pathways as determined by the application of enzymatic hydrolysis, FAB-MS, and 1H- and 13C-NMR spectroscopies. The in vitro metabolism of this 2-pyridinone derivative with rat liver slices resulted primarily in hydroxylation at the 6-methyl and 5-ethyl groups. The 6-hydroxymethyl- and 5-alpha-hydroxyethyl analogs were also inhibitors of HIV-1 reverse transcriptase.

Animals↗

PubMedDate not supplied

Urinary metabolites of amitriptyline in the dog.

Dogs excreted approximately 45% of an oral dose of 14C-amitriptyline (30 mg/kg) in the urine in 24 hr. Two new urinary metabolites of the drug were identified as dihydrodiol derivatives of amitriptyline and nortriptyline, respectively. The major metabolite in dog urine was 10-hydroxyamitriptyline, excreted mainly in conjugated form. Other metabolites were characterized as 10-hydroxynortriptyline, amitriptyline N-oxide, and nortriptyline. Together, these metabolites accounted for approximately 47% of the urinary radioactivity.

Amitriptyline↗

PubMedDate not supplied

Epoxide metabolites of protriptyline in rat urine.

Two epoxide metabolites of 5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (protriptyline) were identified in the urine of rats given 14-C-labeled drug. They were characterized by mass spectrometry, nuclear magnetic resonance spectrometry, and chemical reactivity as 10,11-dihydro-10,11-epoxy-5(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene (I) and 10,11-dihydro-10,11-epoxy-5(3-aminopropyl)-5H-dibenzo[a,d]cycloheptene (II). Over twice as much I as II was excreted and together the two metabolites accounted for approximately 40% of the urinary radioactivity.

Animals↗

PubMedDate not supplied

Human metabolism of cyproheptadine.

Gas-liquid chromatographic and mass, nuclear magnetic resonance, and infrared spectrometric techniques were utilized to identify some of the metabolites of cyproheptadine in the urine of human subjects who had ingested radiolabeled drug. Aromatic ring hydroxylation (followed by glucuronide conjugation), N-demethylation, and heterocyclic ring oxidation were shown to occur in man. The principal metabolite, however, was identified tentatively as a quaternary ammonium, glucuronide-like conjugate of cyproheptadine. No evidence was found for metabolic changes at the tricyclic ethylene bridge in this species.

Chromatography, Gas↗

PubMedDate not supplied

Metabolism of cyclobenzaprine in the dog.

Ten metabolites of cyclobenzaprine, accounting for approximately 50% of the urinary radioactivity, were identified in the urine of dogs to which the labeled drug had been given orally. These included the 1,2-dihydrodiol, three phenolic derivatives, the N-oxide, the 10,11-epoxide, the 10,11-glycol, desmethylcyclobenzaprine, and the glucuronide conjugates of desmethylcyclobenzaprine and cyclobenzaprine. The metabolites were excreted in both the free and conjugated states. Unchanged cyclobenzaprine was present in only minor amounts.

Amitriptyline↗

PubMedDate not supplied

The metabolism of (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid in chimpanzee and man.

The metabolism of the polyvalent saluretic agent (2-cyclopentyl-6,7-dichloro-2-methyl-1-oxo-5-indanyloxy)acetic acid was studied in chimpanzee and man. The drug was well absorbed and extensively metabolized by man. Peak levels of drug (5--8 microgram/ml) occurred within 1.5--4.5 hr of drug administration. The plasma half-life was estimated to be 2 hr; a similar half-life was observed in the chimpanzee. Little unchanged drug (less than 10%) was excreted in the urine of either species. Similar metabolic profiles were obtained for man and chimpanzee. The major urinary metabolites resulted from hydroxylation of the cyclopentyl moiety, giving rise to a number of diastereomers. The alcohol metabolites were subsequently oxidized to the ketone. The excretion of the metabolites coincided with maximal excretion of sodium and chloride ions. The hydroxylated metabolites have intrinsic pharmacological activity.

Animals↗

PubMedDate not supplied

Metabolic disposition of ivermectin in tissues of cattle, sheep, and rats.

The metabolic disposition of ivermectin, a new antiparasitic drug, has been studied in cattle, sheep, and also in rats dosed with the drug labeled with tritium in the C-22,23 positions. In the edible tissues of these animals, the unaltered drug was the major tissue residue component and was quantitated by HPLC-reverse isotope dilution assay. The depletion half-lives of the drug ranged between 1 and 6 days, similar to those of the total tissue residue in these species. Most metabolites present in the liver tissues were more polar than the parent drug. Based on spectral (NMR, mass spectrometric) analysis and chromatographic comparison with authentic compounds prepared by in vitro rat or steer microsomal incubations, three of these metabolites have been isolated and identified as the hydroxylation derivatives of ivermectin, i.e. 24-hydroxymethyl-H2B1a, its monosaccharide, and 24-hydroxymethyl-H2B1b.

Adipose Tissue↗