Biomedical subjects

W Sadée

Publications and source records attributed to W Sadée.

At least 145 records · Page 8Linked to original sources

PubMed1976

Effects of enzyme induction and inhibition on microsomal oxidation of 1,4-benzodiazepines.

Metabolic oxidative profiles of diazepam (I) were obtained by aromatic C-4'-hydroxylation, N-1-demethylation, and 3-hydroxylation using a supernatant of rat liver. Incubation of 3-methyldiazepam (VI), which suppressed 3-hydroxylation, and N-1-nor-3-methyldiazepam (VII), were used to separately investigate these three oxidative pathways. Treatment of animals with phenobarbital enhanced N-1-demethylation and 3-hydroxylation, and to a variable extent C-4'-hydroxylation. Application of metyrapone reduced metabolite formation by 3-hydroxylation and N-1-demethylation, but had no effect on C-4'-hydroxylation. Metyrapone inhibition was more pronounced following than prior to phenobarbital treatment. C-2-hydroxylation was studied using medazepam (XX) incubations. This pathway was increased by phenobarbital pretreatment and reduced by metyrapone inhibition which was again more pronounced following than prior to phenobarbital pretreatment. These results support earlier conclusions on the heterogeneity of liver microsomes and suggests the presence of different species of hepatic microsomal terminal oxidases. Phenobarbital treatment and metyrapone change the metabolic profile via induction and inhibition, respectively, and, thus, in the case of 1,4-benzodiazepines, the formation of metabolites with varying pharmacological activity. This could become important in clinical situations as a diagnostic mean to determine induction under various treatment or, possibly, during cumulation of metabolites with a long half-life.

Animals↗

PubMed1976

Chemical structure and aldosterone receptor affinity of canrenoate-potassium metabolites in rabbits.

Two new major metabolites of canrenoate-potassium (III) were isolated from rabbit livers, in addition to the known metabolite canrenone (II). One metabolite (MA) contains two additional oxygen atoms of unknown location. The second metabolite (MB), which was previously shown to interfere with a plasma aldosterone radioimmunoassay, is identified as 20-hydroxy canrenone. Canrenone (II) and metabolite MB showed significant affinity to rat kidney cytosol aldosterone receptors and might both contribute to the pharmacological effects of canrenoate-K (III).

Animals↗

PubMed1976

Determination of ftorafur and 5-fluorouracil levels in plasma and urine.

A gas chromatographic method was developed for ftorafur (Ft) detection in plasma and urine with a sensitivity of 1 mug/ml. Specific determination of its metabolite 5-fluorouracil (FU) with a sensitivity of 1 ng/ml was achieved by column chromatographic separation from Ft and subsequent gas chromatography-mass spectrometry of bis-silyl-FU in the selected ion mode (GC-MS-SIM) using bis-15N-FU as internal standard. Intravenous injections of 2-14C-Ft and 2',5'-14C-Ft were given to rats and rabbits respectively, and plasma and urine were analyzed for Ft, and 14C activity. Unchanged Ft accounted for most of the 14C activity in plasma, while FU concentrations were below 0.15% and 0.4% relative to Ft concentrations in the rabbit and the rat, respectively. 30-60% of the urinary 14C activity was unchanged Ft and less than 0.2% FU. The significance or low FU levels is discussed in view of the hypothesis that Ft acts as a transport form of its metabolite FU.

Animals↗

PubMed1975

Determination of (plus or minus)-1, 2-bis(3, 5-dioxopiperazinyl) propane plasma levels in rats, rabbits, and humans by GLC and mass fragmentography.

Specific assay procedures were developed to measure plasma concentrations of (plus or minus)-1, 2-bis(3, 5-dioxopiperazinyl) propane (1) by GLC using flame-ionization detection with a sensitivity limit of 5 mug/ml and by GLC-mass fragmentography with a sensitivity limit of 0.2 mug/ml. Applicability of the assay procedures was demonstrated in rats, rabbits, and humans. Plasma concentration-time curves of total 14-C activity and intact I was obtained in rats and rabbits following oral and intravenous administration of 14-C-I. Plasma elimination half-lives of I in the first 2 hr following intravenous doses in rats were 40 and 45 min in two rats. Plasma levels of I were measured over 6 hr after an intravenous dose in rabbits and followed a two-compartment open model with a terminal loglinear plasma half-life of 85 min. Significantly higher total 14-C levels compared to intact I plasma concentrations indicated rapid biotransformation in both rats and rabbits to unknown metabolites. The oral bioavailability appeared to be limited in both species relative to intravenous administration. Two patients receiving 3 g I/m-2 in tablets orally showed plasma levels of I similar to those obtained after oral doses in rats and rabbits, with peak concentrations at 2 hr after the dose (3.8 mug/ml) and with still measurable levels 12 hr after the dose (0.4 mug/ml).

Administration, Oral↗

PubMed1975

Aldosterone plasma radioimmunoassay interference by a spirolactone metabolite.

The plasma aldosterone radioimmunoassay developed by Ito et al. was found to be non-specific for aldosterone following administration of the spirolactones, spironolactone and canrenoate-K, in rabbits, dogs and humans. The assay interfering principle was identified as a hydroxylated derivative (M-B) of canrenone, which itself is a metabolite common to both spironolactone and canrenoate-K. The metabolite M-B possessed a high cross-reactivity to the 21-hemisuccinate aldosterone antibody relative to other spirolactones. A modified procedure was developed specific for plasma aldosterone in the presence of M-B. Following single doses of spironolactone and canrenoate-K, aldosterone plasma levels were unchanged in humans and in dogs and decreased in rabbits.

Aldosterone↗

PubMed1974