Biomedical subjects

L Renberg

Publications and source records attributed to L Renberg.

23 records · Page 2Linked to original sources

PubMedDate not supplied

Stereoselective disposition of RS-tocainide in man.

The disposition of RS-tocainide in three healthy volunteers has been studied after oral administration of a pseudoracemic mixture containing S(+) [3H] tocainide as a radioactive tracer together with a therapeutic dose of the racemate. Analytical methods based on HPLC have been developed to measure S(+) and R(-) tocainide in urine samples. Selected ion detection has been used for quantification of a tocainide conjugate. The radioactive dose was efficiently absorbed and mainly cleared via the kidneys. The elimination half-life of RS-tocainide was found to be 14.3 hours. The elimination half-lives of the two stereoisomers of tocainide differed significantly, i.e. R(-) tocainide 10 hours, and S(+) tocainide 16.7 hours. The observed t1/2 for the tocainide conjugate of 10.3 hours was close to that of R(-) tocainide, indicating that the metabolite was preferably formed from the R(-) stereoisomer of tocainide. Of the given dose, between 45 and 70% can be accounted for.

Adult↗

PubMedDate not supplied

Determination of a renin inhibitor in plasma by solid-phase extraction using acetone as protein binding displacer followed by on-line high-performance liquid chromatography.

H 218/54 is a potent inhibitor of human renin activity (pIC50 = 8.3 at pH 6) and is therefore a potential agent for blood pressure reduction. This lipophilic compound is highly bound to plasma proteins, e.g. 99.7% in rats and 99.6% in humans. For pharmacokinetic studies, a quantitative assay for 3H-H 218/54 in plasma has been developed. On top of an AASP phenyl solid-phase cartridge 70 microliters of rat plasma or 1 ml of cynomolgus plasma was mixed with 200 microliters of water containing 20% acetone. The acetone displaced the substance from plasma proteins without precipitation of the sample and clogging of the extraction column. The mixture was passed through the cartridge, which adsorbed 3H-H 218/54. The cartridge was placed in an AASP autosampler connected to a reversed-phase LC system, with a Vydac C-18 column and CH3CN-H2O-TFA (60:40:0.1, v/v/v) as mobile phase. The effluent from the separation column was collected in fractions for radioactivity counting. Recovery, as measured after adding various amounts of tritium-labelled H 218/54 to blank plasma followed by repeated analysis of the samples, was close to 100% with relative standard deviations between 1.4 and 3.0%. At the lowest level tested, 200 dpm per sample, the recovery was 120% with a relative standard deviation of only 10%. The sensitivity of the method will depend on the specific radioactivity of the dose given.

Acetone↗

PubMedDate not supplied

Identification of two main urinary metabolites of [14C]omeprazole in humans.

The excretion and metabolism of [14C]omeprazole given orally as a suspension was studied in 10 healthy male subjects. An average of 79% of the dose was recovered in the urine in 96 hr, with most of the radioactivity (76% of dose) being eliminated in the first 24 hr. Pooled urine (0-2 hr) from five subjects, containing about 47% of the dose, was analyzed by reverse phase gradient elution LC with radioisotope detection. Omeprazole was completely metabolized to at least six metabolites. The two major metabolites were extensively purified by LC and their structures were determined by MS with derivatization and use of stable isotopes, 1H NMR, and comparison with synthetic references. They were formed by hydroxylation of a methyl group in the pyridine ring, followed by further oxidation of the alcohol to the corresponding carboxylic acid. Both metabolites retained the sulfoxide group of omeprazole, rendering them as unstable as the parent compound at pH less than 7. They accounted for approximately 28% (hydroxyomeprazole) and 23% (omeprazole acid) of the amount excreted in the 0-2-hr collection interval. Based on in vitro studies with the synthetic metabolites in isolated gastric glands, it is unlikely that M1 and M2 will contribute to the pharmacological effect of omeprazole in humans.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMedDate not supplied

Comparative metabolic disposition of oral doses of omeprazole in the dog, rat, and mouse.

The metabolic disposition of [14C]omeprazole was studied in dogs, rats, and mice after the administration of pharmacologically active, single oral doses of drug in buffer solutions (pH 9). Averages of 38% (dogs), 43% (rats), and 55% (mice) of the radiolabeled doses were excreted in the urine in 72 hr. Most of the remaining dose was recovered in the feces. Omeprazole was extensively metabolized in all species studied and the metabolites were eliminated rapidly. No unchanged drug could be detected in the urine samples (less than 0.1% of dose). In each species at least 10 metabolites were detected in urine (pH 9) by gradient elution reverse phase HPLC. Based on liquid chromatographic retention data, the metabolic patterns were very complex and exhibited some quantitative differences between species. Bile was collected from rats and from chronic bile-fistulated dogs. Biliary excretion was a major route of elimination of omeprazole metabolites, and four polar metabolites were detected in the rat bile. The stability of omeprazole metabolites at varying pH values is discussed with reference to reductive metabolism of the parent compound.

Administration, Oral↗

PubMedDate not supplied

Presystemic elimination of the beta-blocker pafenolol in the rat after oral and intraperitoneal administration and identification of a main metabolite in both rats and humans.

Pafenolol is a beta 1-adrenoreceptor antagonist exhibiting some interesting oral absorption properties in both rat and humans. The blood concentration-time profile exhibits two peaks, and the bioavailability is low and dose-dependent due to an incomplete and nonlinear intestinal uptake. The origin of the presystemic metabolism was studied in rats after oral and intraperitoneal administration of tritium-labeled pafenolol with reference to the intravenous route by means of urinary excretion data of pafenolol and metabolites specifically assayed by HPLC and radioisotope detection. The oral-bioavailability increased from 15.8 +/- 4.1% (1.0 mumol/kg) to 33.3 +/- 5.8% (25 mumol/kg, p < 0.001). This was primarily due to a change in the fraction of the absorbed dose (fa) from 21.9 +/- 4.6 to 39.5 +/- 7.9% (p < 0.01). The bioavailability following an intraperitoneal dose was almost complete indicating that the presystemic metabolism was due to gut wall metabolism. Saturation of the presystemic metabolism contributed only by approximately 15-20% to the 2-fold increase of bioavailability. This clearly indicates that the underlying mechanism for the low and dose-dependent bioavailability was an incomplete and nonlinear intestinal uptake. The metabolic pattern showed that at least eight metabolites are formed in the rat. One of these is an alpha-OH pafenolol, identified as the main metabolite in human urine by mass spectrometry.

Administration, Oral↗