Biomedical subjects

G A Hoyer

Publications and source records attributed to G A Hoyer.

24 records · Page 2Linked to original sources

PubMedDate not supplied

The pharmacokinetics and biotransformation of 14C-lisuride hydrogen maleate in rhesus monkey and in man.

14C-labelled lisuride hydrogen maleate was administered intravenously (25 micrograms) and orally (200 micrograms) to three male and three female elderly volunteers. Following i.v. injection radioimmunologically determined plasma levels of unchanged lisuride showed a three-phasic decline with half-lives of 3 minutes, 16 minutes and 2.9 hours. The total clearance was 16 +/- 9 ml/min/kg. Bioavailability was estimated to be 14% of oral dose. Determination of 14C-radioactivity did not show any specific enrichment of lisuride metabolites in cellular components of blood. The drug was almost totally metabolized and its degradation products were eliminated equally via the kidney and liver. Total recovery was about 90% of dose. The elimination half-life was 10 hours. Small parts of the dose administered were renally excreted with a half-life of 23 hours. Lisuride is metabolized extensively. HPLC radiochromatograms of freely extractable metabolites from urine did not show marked differences between both routes of administration. More than 15 compounds were freely extractable, only one of them represented more than 5% of dose. Phase II reactions were quantitatively unimportant. From rhesus monkey urine 6 metabolites were isolated. Chemical structures were proposed for 5 of them. They were assigned to the pattern of freely extractable human urinary metabolites and covered about 50% of radiolabel corresponding to about 13% of dose. The main freely extractable urinary metabolite was thought to be the 2-keto-3-hydroxy-lisuride derivative. Structures of the other four metabolites and earlier observations on the stability of the N'-ethyl-3H label led to the interpretation of independent changes of lisuride by different enzymatic processes such as oxidative N-deethylation, hydroxylation of the benzene system, monooxygenation at C2 and C9, and oxidation of double bonds at C2/C3 and C9/C10.

Animals↗

PubMedDate not supplied

Metabolism of dexamethasone: sites and activity in mammalian tissues.

We have used in vitro techniques to study the metabolism of dexamethasone. Tissue slices, homogenates and microsomal fractions of various mammalian organs from rats and humans have been used. We focused particularly on the question of whether or not dexamethasone (Dexa) is oxidized at the C11-OH group by 11 beta-hydroxysteroid-dehydrogenase. High activities of this enzyme system for Dexa were localized in renal cortex and rectum. Material from both human and murine liver was ineffective. The main metabolite formed from Dexa in renal and intestinal systems was identified by different mass-spectrometric techniques including on line HPLC mass spectrometry as 11-dehydro-dexamethasone. This finding was corroborated by the observation that both corticosterone and glycyrrhetinic acid block the metabolic transformation of Dexa.

Animals↗

PubMedDate not supplied

Identification of the major metabolites of the prostaglandin E2-analogue sulprostone in human plasma, and isolation from urine (in vivo) and liver perfusate (in vitro) of female guinea-pigs.

After the parenteral administration of the 3H-labeled prostaglandin E2-analogue (PGE2-analogue) to three healthy women, a number of metabolites were observed in the plasma, some of them still potentially pharmacologically active. The metabolite pattern in human plasma was very similar to the one observed in the urine of female guinea pigs, which received a total dose of 0.21 mg [3H]sulprostone by repeated sc administration over a period of 5 days. In vitro perfusion of an isolated guinea pig liver with 50 mg of [3H]sulprostone, dissolved in Tyrode's solution, yielded another source for the isolation of those metabolites, which were also present in human plasma. Both urine and perfusion medium were submitted to repeated HPLC-separations and the recovery during the purification procedure was calculated for each metabolite on the basis of recovered radioactivity after each step of purification. Chromatographically pure metabolites were submitted to GC/MS analysis, 1H-NMR and IR spectroscopy for structural elucidation. Besides the unchanged parent compound, four metabolites of sulprostone could be identified in human plasma by co-chromatography with the isolated compounds. One of two major metabolites was the PGA2-analogue of the parent drug, the other was a cyclization product of the beta-side chain of sulprostone with the cyclopentenone ring, preceded by delta 13 reduction. The two minor metabolites were the free acids of sulprostone and the PGA2-analogue.

Abortifacient Agents, Nonsteroidal↗

PubMedDate not supplied

Biotransformation of the stable prostacyclin analogue, iloprost, in the rat.

The metabolic pathway of the stable prostacyclin analogue, iloprost (ZK 36 374), was studied in the rat, both in vivo and in vitro by a rat liver perfusion model. Metabolites were isolated from both experiments by preparative high performance liquid chromatography and identified by GC/MS and NMR analysis. In vitro, iloprost was metabolized by consecutive beta-oxidation of the upper side chain. Both dinor- and tetranoriloprost could be isolated from the perfusion medium. The metabolic pattern in bile was similar to that in the perfusion medium. In vivo, iloprost was totally metabolized by beta-oxidation of the upper side chain and by subsequent hydroxylation and conjugation. The compounds identified in rat urine were tetranoriloprost which represented about 3/4 of all metabolites, hydroxylated tetranoriloprost with the additional hydroxyl group presumably at position 17 and a conjugate of tetranoriloprost. Dinoriloprost and unchanged drug were not observed. beta-Oxidation of the upper side chain was stereoselective to give a 6 alpha-H/6 beta-H ratio of 86:14.

Animals↗

PubMedDate not supplied

Biotransformation of proterguride in the perfused rat liver.

The metabolic pathway of the dopaminagonistic ergoline derivative, proterguride, was studied in vitro in a rat liver perfusion experiment. Metabolites were isolated by preparative HPLC and identified by MS and NMR analyses. In total, seven compounds could be identified. The metabolic steps involved in the biodegradation of proterguride are N-deethylation, N-oxidation, hydroxylation, and/or dehydrogenation and oxidative cleavage of the indole ring.

Animals↗

PubMedDate not supplied

Biotransformation of the antidepressant DL-rolipram. I. Isolation and identification of metabolites from rat, monkey, and human urine.

The metabolic pathway of DL-rolipram was studied in two animal species and in man. Metabolites were isolated from rat, rhesus monkey, and from human urine by preparative HPLC and identified by MS and NMR analysis. In total, the structures of 7 degradation products could be elucidated. Rolipram was metabolized by ether cleavage at the methoxy and cyclopentyloxy groups and by hydroxylation in positions 2 or 3 of the cyclopentyloxy ring followed by sulphation. Additionally, but exclusively in man, the 5-position of the pyrrolidone ring was hydroxylated.

Animals↗