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S Keiding

Publications and source records attributed to S Keiding.

At least 73 records · Page 4Linked to original sources
PubMed1985

Species differences of galactose metabolism in erythrocytes.

Galactose metabolism was studied in suspensions of erythrocytes from man, rat, ox and pig at approximate steady-state galactose concentrations from 0.1-6.5 mmol/l. There was no detectable galactose elimination in pig erythrocytes. In the three other species the elimination followed saturation kinetics with the maximal elimination rate, Vmax, being 8.0 mumol . min-1 . l-1 human erythrocytes; 12 mumol X min-1 . l-1 rat erythrocytes; 2.4 mumol . min-1 . l-1 bovine erythrocytes. The half saturation concentration, Km, was about the same in all three species, around 0.2 mmol/l. If similar in vivo, erythrocyte metabolism of galactose is not of major quantitative importance compared to the hepatic metabolism in the species examined.

Animals↗
PubMed1984

Current models of hepatic pharmacokinetics: flow effects on kinetic constants of ethanol elimination in perfused rat liver.

At present two different pharmacokinetic models of the enzymic elimination of substances from the blood flowing through the liver are used: the sinusoidal perfusion model assuming the elimination to take place at the local sinusoidal blood substrate concentration, falling continuously from the inlet to the outlet of the sinusoid, and the venous equilibration model assuming elimination at the hepatic outlet concentration. It is an ultimate requirement of such models that the estimates of the enzymic parameters Vmax and Km be independent of variations in hepatic blood flow rate. This was used to compare the two models experimentally. Ethanol was given at two successive constant infusion rates (7 and 10 mumol/min) to 11 livers from rats (200 g) perfused by a recirculating medium. In each of the infusion periods the hepatic blood flow rate was varied experimentally (10 and 17 ml/min, respectively). From the measured steady-state ethanol concentrations in the hepatic inlet and outlet, Km and Vmax were calculated from both models at both low and high blood flow rates. The Km calculated according to the venous equilibration model was significantly lower in the low-flow than in the high-flow periods (P less than 0.05); this model is thus not consistent with data. Vmax values were not influenced by hepatic blood flow. The Km calculated according to the sinusoidal perfusion model were not influenced by flow (P less than 0.5) and Vmax was also unchanged. The sinusoidal perfusion model is thus not inconsistent with data.

Animals↗
PubMed1984

Femoxetine clearance in patients with liver cirrhosis.

The pharmacokinetics of femoxetine (a 5-HT uptake inhibitor with antidepressive effect) was studied in 12 patients with liver cirrhosis and in 6 healthy controls after a single oral dose of femoxetine HC1. The average blood concentration of femoxetine, as assessed by the values of AUC (area under the plasma concentration/time curve), was significantly higher in the patients with liver cirrhosis than in the healthy controls in spite of dose reduction in the patients. The elimination half-life of femoxetine was within the normal limits in most of the patients. The oral clearance of femoxetine was considerably lower in patients, (0.65-4.02 1/hr/kg) than in the controls (8.13- greater than 50 1/hr/kg). It was not directly related to the metabolic function of the liver, measured as the galactose elimination capacity being 0.015-0.024 mmol/min./kg and 0.033-0.041 mmol/min./kg, respectively. When treating patients with reduced liver function, it is recommended to reduce the doses and to monitor closely the plasma levels.

Adult↗
PubMed1984

Galactose elimination kinetics in perfused rat liver after two thirds hepatectomy.

Galactose elimination kinetics was studied in isolated perfused livers (single pass) from rats subjected to two thirds partial hepatectomy 6 h earlier or immediately before investigation. No difference was found between the two groups in the maximum galactose elimination rate or in the half saturation galactose concentration. This is in contrast with in vivo observation of restored galactose elimination capacity 6 h after two thirds hepatectomy. The discrepancy indicates that extrahepatic factors may be of importance for the metabolic regulation in the liver during regeneration.

Animals↗
PubMed1984

Flow dependence of propranolol elimination in perfused rat liver.

The effect of experimental variations of the blood flow rate on hepatic elimination of propranolol was studied in livers from 200 g rats perfused in a recirculating system given a constant infusion of propranolol into the reservoir throughout each experiment. This design ensures that, at steady state, the elimination rate of propranolol is the same as the infusion rate of propranolol, and equal to the hepatic blood flow rate multiplied by the hepatic inlet to outlet propranolol concentration difference. Thus, when flow is increased, the concentration difference will decrease, and vice versa. It is currently a matter of debate whether or not this change in concentration difference will influence the outlet substrate concentration. The venous equilibration model (Rowland et al., J. Pharmacokinet. Biopharm. 1: 123-136, 1973) predicts that at a given elimination rate, the outlet concentration is flow-independent, whereas the sinusoidal perfusion model (Bass et al., J. Theor. Biol. 61: 393-410, 1976) predicts that both inlet and outlet concentrations will change. In 13 of 14 experiments, increasing the flow rate (from an average 9 to 14 ml/min) resulted in a decrease of the inlet concentration and elevation of the outlet concentration (each P less than .005). Thus, the data reject the venous equilibration model but are consistent with the sinusoidal perfusion model under the experimental conditions investigated.

Animals↗
PubMed1983

Ethanol metabolism in heavy drinkers after massive and moderate alcohol intake.

Some alcoholics have a regular daily alcohol consumption of more than 100 g. In preliminary observations we had the impression that the claimed alcohol intake in such 'heavy drinkers' was higher than could be accounted for by the ethanol elimination rate as measured routinely at 10 mmol/l (0.5 g/l). We therefore measured the ethanol elimination rate at very high blood ethanol concentrations of 40-80 mmol/l (2-4 g/l) found in eight alcoholics following heavy alcohol intake by measuring the falling blood ethanol concentrations until being less than 1 mmol/l. The elimination rate, on average 83 mumol/min per 1 blood, was about 49% higher than the elimination rate measured at 10 mmol/l in the same subject, being on average 58 mumol/min per 1/blood (paired t-test, P less than 0.05). The elimination rate following the high initial ethanol concentrations remained high until the concentration was below 5 mmol/l. Calculations of elimination rates are based on a number of assumptions concerning the physiologic and metabolic conditions. We examined specifically if the concentration-time curves could be adequately described by assuming metabolism according to a Michaelis-Menten pathway with a low Km value (simulating alcoholdehydrogenase with Km 0.2 mmol/l) or by assuming metabolism by two pathways with an alternative high-Km pathway with Km about 10 mmol/l. It was not necessary, in the statistical analysis, to include an alternative high-Km pathway. On the other hand, the data does give room for up to 50% elimination via such alternative pathways. The elimination rate at the high concentrations corresponded roughly to the claimed daily alcohol intake; furthermore the measured elimination rate at the lower concentrations were similar to values in non-alcoholics.

Alcohol Drinking↗
PubMed1983

Kinetics of galactose uptake by perfused rat livers: applicability of a family of models.

Mathematical models for general substrate uptake mechanisms in the liver have been used to describe the kinetics of galactose removal. In this study sets of galactose uptake rates to galactose concentration relations obtained by perfusion of ten livers of 200 g rats were examined. The rate of galactose uptake (v) was related to the galactose concentration in the sinusoids (calculated as the logarithmic mean of in- and outlet concentration, ĉ). In all experiments a saturation pattern emerged, but the resulting 1/v versus 1/ĉ plots were all markedly convex, discarding simple Michaelis-Menten kinetics. Data were therefore examined in the light of a family of kinetic models, including the following modifications: substrate inhibition, porto-systemic shunting, and allosterism. The kinetic constants were assessed by iterative procedures, aiming at linearization of the double reciprocal plots. The two latter models were found to fit the experimental data by entering a shunting of 61% of the hepatic blood flow, or two active sites, respectively. Since this degree of shunting is improbable the results speak in favour of allosterism. The work gives an example of whole-liver kinetic considerations when simple Michaelis-Menten is insufficient.

Allosteric Regulation↗
PubMed1983

Hepatic elimination of femoxetine in pig.

Hepatic elimination of femoxetine was studied in seven anaesthetized 40 kg pigs by means of constant rate infusions of 3-41 mg/min. (8.6-118 mumol/min.) into the portal vein. The elimination followed saturation kinetics (Michaëlis-Menten constants: Vmax 12 mg . min.-1 . kg-1 liver; Km 1.3 mg . 1-1 blood) and was characterised by high hepatic extraction, due to metabolism. The hepatic output of the active metabolite, nor-femoxetine, was very low, indicating that other metabolic pathways than demethylation were more important in the pig. The high hepatic elimination in the pig corresponds to the high first pass effect, earlier found in man, and it depends upon the infusion rate as well as the total dose.

Animals↗
PubMed1983

Hepatic elimination of femoxetine in pig during intravenous infusion.

Hepatic elimination of femoxetine was studied in six anaesthetized pigs during intravenous administration. Femoxetine was given into a jugular vein as a constant infusion of 0.4-7.2 mg/min. in five pigs and as a bolus injection of 383 mg in one pig. The hepatic extraction was high (92-98%) corresponding to earlier findings of 91-99% when femoxetine was infused into the portal vein in pig or given orally to man. The urinary excretion was low, less than 5% of the dose, and the estimated extrahepatic metabolism was not significantly different from zero.

Animals↗
PubMed1982

Hepatic elimination of endogenous gastrin in pigs.

To assess hepatic elimination of gastrin, concentrations of gastrin were determined radioimmunochemically in plasma samples collected simultaneously in six pigs from the portal vein, hepatic vein, and a peripheral artery before and after stimulation of the antrum with meat extract. The portal plasma flow and the total plasma volume were measured. During meat extract stimulation the antral release of gastrin increased significantly (p less than 0.05), from 15.9 +/- 3.4 ng/min to 35.6 +/- 5.4 ng/min, and the hepatic elimination increased significantly (p less than 0.05), from 10.4 +/- 2.8 ng/min to 25.5 +/- 5.9 ng/min (mean +/- S.E.M., six pigs). The artery to mesenteric vein concentration ratio was 1.03 +/- 0.05 in the basal and 0.97 +/- 0.10 in the stimulated period, indicating neither release nor uptake of gastrin in the intestines of five pigs. Hepatic elimination of gastrin was roughly proportional to the gastrin concentrations in portal venous plasma. The mean hepatic plasma clearance of gastrin was 148 +/- 26 ml/min and the total body clearance 268 +/- 43 ml/min. Thus extrasplanchnic gastrin removal accounted for half of total body elimination. It is concluded that in anesthetized pigs the "first-pass" effect on portal gastrin content makes the liver one of the important sites for elimination of endogenous gastrin.

Animals↗
PubMed1982

Hepatic galactose elimination kinetics in the intact pig.

The hepatic galactose elimination kinetics was studied in eight anaesthetized pigs by hepatic vein catheterization. Galactose was given as successive constant intravenous infusions so that steady-state concentrations, ranging from 50 mumol/l to 8 mmol/l, were obtained. Concentrations were measured in a peripheral artery and in the hepatic veins. Hepatic blood flow was determined by constant infusion of indocyanine green. The elimination kinetics is described by a mathematical model which assumes that the liver sinusoids are perfused with unidirectional blood flow and that the elimination in the hepatocytes takes place according to Michaelis-Menten kinetics. This creates a decreasing sinusoidal blood concentration from the inlet to the outlet of the liver. The estimated maximal elimination rate, Vmax, was on average 0.67 mmol min-1 kg-1 liver (range 0.55-0.95) and the half saturation concentration Km 0.25 mmol/l (0.12-0.58). The estimate of Km is similar to the value found in the isolated perfused pig liver (0.23 mmol/l), whereas the estimate of Vmax is about 50% higher (0.43 mmol min-1 kg-1 liver), probably due to both extrahepatic elimination in the splanchnic area and a better function of the liver in situ than in the isolated preparation.

Animals↗
PubMed1981

Cytophotometry of liver cells from ethanol-fed rats: ethanol causes increased polyploidization and protein accumulation.

Cellular protein and DNA content were determined by Feulgen--Naphthol Yellow S cytophotometry on isolated liver cells from rats fed ethanol for 2--6 months. It was found that parenchymal liver cells after ethanol feeding contained 13% more protein than cells of the same ploidy class from controls; that the average parenchymal cell in ethanol-fed rats contained 16% more protein than in controls due to the increased occurrence of polyploid cells; that the protein accumulation develops over 2 months, does not progress thereafter and disappears after a few days of reduced ethanol intake; that the tendency to form polyploid cells is accentuated during liver regeneration. It is suggested that the effect of alcohol on microtubular function, which is regarded as the cause of the protein accumulation, may also bring about increased polyploidization.

Animals↗
PubMed1980

Importance of flow and haematocrit for metabolic function of perfused rat liver.

The influence of flow rate and haematocrit on the metabolic function of once-through perfused rat liver, as assessed by galactose elimination and oxygen uptake, was studied. Rats weighting from 195 to 220 g were used. Each of eleven experiments consisted of four periods; the blood flow rate was 10 ml/min in the first and the last period, and it was varied at random from 0.6 to 18 ml/min in the second and the third period. Haematocrit values of either 0.40, 0.28 or 0.16 1/1 were constant in each experiment. The input concentration of galactose was 1.7 mmol/l. Both galactose elimination and oxygen uptake were independent of the flow rate between 6 and 18 ml/min. At flow rates below 6 ml/min (i.e. below 0.9 ml/min/g liver) both functions were reversibly decreased in parallel with the flow. The values were highly correlated. There was a trend towards a lower galactose elimination rate and oxygen uptake at lower haematocrit values. It is emphasized that flow rate and haematocrit must be kept above certain limits in metabolic studies with perfused rat liver.

Animals↗