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Biomedical subjects

J Gabrielsson

Publications and source records attributed to J Gabrielsson.

34 records · Page 2Linked to original sources
PubMed1993

Pharmacokinetics of R(+)-terodiline given intravenously and orally to healthy volunteers.

(+)-Terodiline was given orally (25 mg) and intravenously (12.5 mg) to eight healthy volunteers. The pharmacokinetics of (+)-terodiline could be described by a one compartment model. The lag time of absorption was 0.6 +/- 0.5 hr (mean +/- S.D.), the absorption half-life 0.9 +/- 0.5 hr, the time to maximum serum concentration 5.6 +/- 2.2 hr and the corresponding maximum serum concentration 62 +/- 22 micrograms/l. The volume of distribution was found to be 372 +/- 84 1, the systemic clearance 86 +/- 29 ml/min., the mean residence time 81 +/- 38 hr and the observed terminal half-life of elimination 56 +/- 26 hr. The urinary excretion of the intravenous dose was 12 +/- 6% and the renal clearance 10 +/- 5 ml/min. The bioavailability of (+)-terodiline was 93 +/- 19%. The present results indicate that (+)-terodiline as well as the racemate can be characterized as low clearance long half-life drugs. One subject was a poor hydroxylator of debrisoquine and exhibited a 3-fold decrease in clearance and increase in half-life of (+)-terodiline relative to extensive metabolizers. Observed pharmacological effects were mild accomodation disturbances and dry mouth, i.e. the same effects as those that may be seen at a corresponding dose of terodiline given as a racemic mixture.

Absorption↗
PubMed1992

Determination of potato glycoalkaloids and their aglycone in blood serum by high-performance liquid chromatography. Application to pharmacokinetic studies in humans.

The development of a high-performance liquid chromatography (HPLC) method for the separation and quantification of potato glycoalkaloids and their aglycone solanidine in blood serum is reported. High selectivity was obtained by using solid-phase extraction followed by off-line dual-column HPLC. Injections were made via a sample enrichment column to achieve maximum sensitivity in the assay. The potato alkaloids in the HPLC effluents were detected by ultraviolet absorption at 200 nm. The detection limits were estimated to be 0.3 ng/ml of serum for each of the alkaloids. The method was used to study the pharmacokinetics of potato glycoalkaloids in humans. alpha-Solanine and alpha-chaconine were detected in all blood serum samples collected from seven volunteers 1-25 h after a meal of potatoes. Solanidine was detected in some samples, but there were no traces of the mono- or diglycosides. The average apparent biological half-lives for alpha-solanine and alpha-chaconine were 11 and 19 h, respectively.

Adult↗
PubMed1990

Effects of dietary sodium selenite supplementation on salicylate-induced embryo- and fetotoxicity in the rat.

The effects of dietary supplementation with sodium selenite (3.0 or 4.5 ppm Se) for 8 weeks prior to and throughout gestation on sodium salicylate induced embryo- and fetotoxicity (resorptions, fetal deaths, malformations, fetal weight reduction) have been studied in the rat. Salicylate was administered either as daily intragastric bolus doses of 250 mg/kg on gestation days 6-13 (maternal peak and trough salicylate levels of 222-120 micrograms/ml whole-blood) or via constant rate intravenous infusion of 150 mg/kg/day on the same gestation days via implanted osmotic minipumps (stable average maternal blood salicylate level of 120 micrograms/ml = human antirheumatic concentration). Both gavage and infusion of salicylate resulted in an increase of resorptions and fetal deaths as well as a decrease of fetal body weights. Gavage with salicylate also produced about 50% malformed fetuses. Selenite did not protect against the embryotoxic effects of salicylate administered as intragastric bolus doses. However, selenite was found to significantly increase fetal survival rate in the infusion experiment, although it did not counteract the decrease of fetal body weight. In animals fed selenite only, no negative effects on fetal body development were noted. The protective effect of selenite against salicylate induced embryotoxicity is difficult to explain, since very little is known about the mechanisms of salicylate embryotoxicity and the biological effects of selenium. However, an interaction between selenium, via glutathione peroxidase, and salicylate at the level of prostaglandin synthesis could be possible.

Animals↗
PubMed1990

2-Nitrofluorene metabolism in the rat lung. Pharmacokinetic and metabolic effects of beta-naphthoflavone treatment.

Absorption, metabolism and DNA binding of 2-nitrofluorene (NF) was studied in isolated, perfused and ventilated rat lungs and in lung microsomal incubations. Comparisons were made between control animals and animals treated with beta-naphthoflavone (BNF), a 2,3,7,8-tetrachlorodibenzo(rho)dioxin (TCDD) receptor ligand and inducer of cytochrome P450IA1. Clearance of NF increased significantly in the isolated, perfused and ventilated lungs after BNF dosage, from 0.55 +/- 0.06 ml/min to 2.37 +/- 0.62 ml/min (P less than 0.05, n = 5-6). As a consequence of this, the mean residence time (MRT) for NF decreased when NF was dosed directly to the perfusion buffer, from 213 +/- 23 min (n = 6) to 48 +/- 9 min (n = 6), and after intratracheal dosage from 289 +/- 101 min (n = 5) to 135 +/- 72 min (n = 5). Irreversible binding of NF metabolites to DNA increased 2-fold after treatment with BNF when NF was dosed to the lung perfusion buffer. Treatment with BNF increased the rate of lung microsomal NF metabolism significantly, from 54 +/- 5 to 106 +/- 11 pmol/min/mg protein (P less than 0.05, n = 6-12). Formation of the monohydroxylated metabolite X-OHNF was inhibited in vitro by addition of alpha-naphthoflavone (50 microM), by 89 and 98% with lung microsomal fractions from control and BNF-treated rats respectively. In contrast, proadifen (50 microM) preferentially inhibited formation of 9-OHNF, by 42 and 33% in incubations with lung microsomal fractions from control and BNF-treated animals. Anti-P450IIB1-IgG inhibited formation of 9-OHNF by 96 and 45% with lung microsomes from control and BNF-treated rats respectively. Formation of X-OHNF was unaffected by addition of anti-P-450IIB1-IgG in both cases. These results show that both constitutive and inducible microsomal rat lung enzymes metabolize NF. A constitutive enzyme, most likely cytochrome P450IIB1, catalyzes metabolic attack on NF with high preference for the 9-position. A BNF-inducible microsomal enzyme, most likely cytochrome P450IA1, catalyzes hydroxylation of NF both in the 9-position and in other positions. Increased metabolic clearance, metabolism and DNA binding of NF after BNF treatment suggest that the level and specificity of cytochrome P450 isozymes may be important determinants for toxicity and availability of NF in the rat lung.

Absorption↗
PubMed1990

Accumulation and turnover of metabolites of toluene and xylene in nasal mucosa and olfactory bulb in the mouse.

Autoradiography of male mice following inhalation of the radioactively labelled solvents, toluene, xylene, and styrene, revealed an accumulation of non-volatile metabolites in the nasal mucosa and olfactory bulb of the brain. Since no accumulation occurred after benzene inhalation, it was assumed that the activity represented aromatic acids, which are known metabolites of these solvents. This was supported by the finding that also radioactive benzoic acid (main metabolite of toluene) and salicylic acid accumulated in the olfactory bulb. High-performance liquid chromatography revealed that after toluene inhalation (for 1 hr), nasal mucosa and olfactory bulb contained mainly benzoic acid, with a strong accumulation in relation to blood plasma, and considerably less of its glycine conjugate, hippuric acid. After xylene inhalation, on the other hand, methyl hippuric acid dominated over the non-conjugated metabolite, toluic acid. The results indicate a specific, possibly axonal flow-mediated transport of aromatic acids from the nasal mucosa to the olfactory lobe of the brain. The toxicological significance of these results remains to be studied.

Animals↗
PubMed1990

Disposition of morphine-3-glucuronide in the pregnant rhesus monkey.

Morphine-3-glucuronide (M3G) is the major metabolite of morphine and is present in the circulation of persons treated with morphine or abusing heroin. This project was designed to study the kinetics of M3G in the foeto-maternal compartment, since this metabolite may be of relevance for the abstinence syndrome observed in neonates of pregnant abusers. The kinetics of M3G were studied in two non-pregnant and four pregnant Rhesus monkeys. M3G was given as a bolus injection in four of the animals and as a long-term infusion for 12 hr in two animals. M3G passed slowly across the placenta to the foetus and amniotic fluid. After 10 hr of M3G infusion, the foetal plasma M3G concentration was measured in two cases and found to be 37% and 72%, respectively, of the maternal concentration.

Amniotic Fluid↗
PubMed1989

A pharmacokinetic model of intravenously administered hyaluronan in sheep.

Hyaluronan (HA: hyaluronic acid) is produced in the interstitium and reaches the blood circulation through the lymph. It is rapidly eliminated by means of specific receptors on liver endothelium. The elimination characteristics of intravenously administered HA were studied in 10 conscious sheep at the normal plasma HA concentration by injection of a 3H-labeled tracer and at a very high concentration by an i.v. infusion of unlabeled HA and simultaneous injection of a tracer dose of 3H-labeled HA. At a normal plasma HA concentration (0.12 +/- 0.05 microgram/ml; range, 0.072-0.228 microgram/ml), the apparent T 1/2 of 3H-HA was 5.3 +/- 1.1 min (range, 3.3-6.5 min). At higher plasma concentrations (range, 1.83-3.35 micrograms/ml), the apparent T 1/2 was considerably prolonged (range, 18.2-43.5 min). A one-compartment, nonlinear model was fitted to data obtained from the bolus-infusion study of unlabeled HA. The Michaelis-Menten constant, Km, was 0.12 +/- 0.04 microgram/ml, indicating that a deviation from linear kinetics will occur when the normal plasma concentration is exceeded. The Vmax was 0.062 +/- 0.009 microgram/ml/min. Three-dimensional surface plots showed that the plasma HA concentration and the total hepatic plasma flow influence the apparent metabolic clearance, extraction ratio, turnover, and T 1/2 of intravenously injected hyaluronan. There was a high correlation between T 1/2 as measured by the injected 3H-HA and T 1/2 calculated from the model (r = 0.96).

Animals↗
PubMed1989

Pharmacokinetics of quinacrine after intrapleural instillation in rabbits and man.

Quinacrine was given by intrapleural instillation or intravenous infusion to 10 rabbits. The uptake of quinacrine from the pleural space was rapid and complete. The mean absorption half-life was approximately 7 min and the mean bioavailability was slightly in excess of 100%. Similar absorption characteristics generally applied in man, in a pilot study on four patients. In three of them, peak quinacrine plasma concentrations were reached that were far above the normal therapeutic range. Known systemic side-effects of quinacrine comprise CNS stimulation, toxic psychosis and convulsions. In view of the high bioavailability and the large doses used for pleural sclerosing (pleurodesis) in patients, neurological disease and psychiatric disturbances that predispose to CNS toxicity should be considered as contraindications to intrapleural quinacrine.

Animals↗
PubMed1988

Clinical pharmacokinetics of clozapine in chronic schizophrenic patients.

The clinical pharmacokinetics of clozapine, an atypical neuroleptic, was evaluated in 10 chronic schizophrenic male patients after intravenous and oral administration. The mean equilibrium-state concentration ratio between blood and plasma was experimentally determined to be 0.87. The average values for blood clearance, hepatic extraction ratio and oral bioavailability were 250 ml/min, 0.2 and 0.27, respectively. Plasma concentration peaked on average at 3 h. The mean volume of distribution at steady-state and the terminal half-life was 1.6 l/kg and 10.3 h, respectively. A large fraction of the dose is most probably metabolized by some extrahepatic presystemic routes. The large inter-individual variability in the bioavailability and clearance is probably the main reason for large variation in the steady-state plasma level in patients receiving the same oral dosage regimen.

Administration, Oral↗
PubMed1988

Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine.

The pharmacokinetics and bioavailability of N-acetylcysteine (NAC) have been determined after its intravenous and oral administration to 6 healthy volunteers. According to a randomized cross-over design each subject received NAC 200 mg i.v. and 400 mg p.o., and blood samples were collected for 30 h. Reduced NAC had a volume of distribution (VSS) of 0.59 l.kg-1 and a plasma clearance of 0.84 l.h-1.kg-1. The terminal half-life after intravenous administration was 1.95 h. The oral bioavailability was 4.0%. Based on total NAC concentration, its volume of distribution (VSS) was 0.47 l.kg-1 and its plasma clearance was 0.11 l.h-1.kg-1. The terminal half-life was 5.58 h after intravenous administration and 6.25 h after oral administration. Oral bioavailability of total NAC was 9.1%.

Acetylcysteine↗
PubMed1987

Constant-rate infusion of nicotine and cotinine. I. A physiological pharmacokinetic analysis of the cotinine disposition, and effects on clearance and distribution in the rat.

The tissue partition of cotinine was measured by a GC-MS method following a 6-day constant-rate input of nicotine and cotinine to male rats by means of an osmotic minipump. The tissue-to-blood partition coefficients of cotinine were calculated for adipose (0.08), brain (0.48), heart muscle (0.51), following the cotinine infusion. When nicotine was infused the tissue partitioning of cotinine increased by a factor of 2.3-4.9, depending on the tissue sampled. Another group of animals were killed at timed intervals from 10 min to 30 hr, after having received a single intravenous bolus dose of 0.5 mg cotinine, and the washout of cotinine was traced in blood and tissues. A physiological model was used to simulate the disposition of cotinine. Generally, the model-predicted concentrations were consistent with those found experimentally. The fractional uptake of cotinine into various tissues was simulated. Blood, intestinal, and skeletal muscle tissues embodied more than 70% of the total body load of the drug. Clearance (Cl), volume of distribution (Vd), and the biological half-life (t1/2) were calculated both from the infusion study and by fitting a monoexponential model to the iv blood data of the rat. Significant differences were found in the apparent clearance calculated from the single iv bolus dose compared to the constant rate infusion. The volume of distribution was, however, consistent from both studies. The impact of a change in clearance was also simulated.

Animals↗
PubMed1987

Pharmacokinetics of i.v. and rectal methohexitone in children.

The pharmacokinetics of methohexitone were investigated in 15 healthy children undergoing minor surgery under inhalation anaesthesia. Six received 1% methohexitone 1-2 mg kg-1 i.v. and nine received 10% methohexitone 20-25 mg kg-1 per rectum. On i.v. administration, three-compartment pharmacokinetics generally applied. The mean elimination half-life of methohexitone was 193 +/- 75 min; that is, considerably longer than previously reported for children, but in good agreement with findings in adults. The mean clearance was 17.9 +/- 8.3 ml min-1 kg-1, the volume of distribution at steady state was 2.1 +/- 0.24 litre kg-1 and the mean residence time was 134 +/- 47 min. The pharmacokinetic model used for the i.v. data was easily modified to suit the plasma concentration curves obtained on rectal administration. The mean bioavailability of methohexitone administered per rectum was 17%, with a six-fold variation between individuals.

Administration, Rectal↗
PubMed1985

Constant rate of infusion--improvement of tests for teratogenicity and embryotoxicity.

Sodium salicylate was used as a model substance to investigate whether the embryotoxic effects on rat fetuses varies between two modes of administration. A marked increase in fetal adverse effects was observed at analgetic doses with the once-a-day bolus regimen compared to the constant rate input. The difference was less marked at antirheumatic levels.

Abnormalities, Drug-Induced↗