The control of sodium excretion following saline infusion in dogs

Summary The increase in fractional excretion of sodium following intravenous infusion of saline has been investigated in dogs fed with sodium-rich or poor diets after transplantation to the neck of these animals of kidneys removed from dogs submitted previously to either diet. The response of in situ and of transplanted organs has been compared in the four possible combinations of perfusors and kidney donors. No significant differences were observed between the four series, for the same net saline load, in arterial and venous pressures, extravascular and intravascular expansion, or blood dilution. The response in each series was independent of extracellular expansion and was best related to the degree of blood dilution. However, the magnitude of the response to the same net saline load depended on a resetting of the sensitivity of the kidney itself to the blood changes, this resetting depending on the previous dietary sodium balance. This sensitivity was related also to the presence in the blood of a potentiating material which might be, at least partly, of renal origin, and which might represent an intrarenal mediator of the natriuretic response.This work has been performed with the help of the Fonds National de la Recherche Scientifique of Belgium.     

Pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after i.v. bolus multiple administration in rats

We investigated the pharmacokinetics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, after intravenous (i.v.) bolus administration at a multiple dose every 24 h for 5 days in rats. To analyze ID-6105 levels in biological samples, we used an HPLC-based method which was validated in a pharmacokinetic study by suitable criteria. The concentrations of ID-6105 after the multiple administration for 5 days were not significantly different from the results after the single administration. The t1/2alpha, t1/2beta, Vdss, and CLt after the multiple administration were not significantly different from the values after the single administration. Moreover, the concentrations of ID-6105 1 min at day 1-5 after i.v. bolus multiple administration did not show the significant difference. Of the various tissues, ID-6105 mainly distributed to the kidney, lung, spleen, adrenal gland, and liver after i.v. bolus multiple administration. ID-6105 concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration. However, the ID-6105 concentrations in various tissues 48 h after i.v. bolus administration decreased to low levels. ID-6105 was excreted largely in the bile after i.v. bolus multiple administration at the dose of 3 mg/kg. The amounts of ID-6105 found in the bile by 12 h or in the urine by 48 h after the administration were calculated to be 14.1% or 4.55% of the initial dose, respectively, indicating that ID-6105 is mostly excreted in the bile. In conclusion, ID-6105 was rapidly cleared from the blood and transferred to tissues, suggesting that ID-6105 might not be accumulated in the blood following i.v. bolus multiple dosages of 3 mg/kg every 24 h for 5 days. By 48 h after i.v. bolus administration, ID-6105 concentrations in various tissues had decreased to very low levels. The majority of ID-6105 appears to be excreted in the bile.     

Toxicokinetics of methyl mercury in pigs

Toxicokinetics of methyl mercury were studied in pigs after intravenous (i.v.) administration of the compound. The distribution of methyl mercury was slow taking 3–4 days to be completed. Blood elimination half-life was found to be 25 days. The apparent volume of distribution was 9.8 l/kg indicating pronounced tissue accumulation of methyl mercury. Highest mercury levels were found in kidney and liver, with lower contents in muscle and brain and very little in adipose tissue. The results indicate that from organs like liver and kidney methyl mercury is eliminated much more slowly than from the blood. Over a period of 15 days 16% of the dose administered was excreted with faeces and 0.9% in the urine.     

Parathormone as a mediator of inorganic phosphate diuresis during saline infusion in the rat

Summary Normal rats were infused with isotonic saline at 0.50 ml/min for 2 hours in order to expand their extracellular fluid volume. Under these conditions fractional excretion of inorganic phosphate was found to be as high as 38.8±3.0% of filtered phosphate, while fractional sodium excretion was 12.9±0.7% of filtered sodium. The combined addition of calcium and magnesium to the infusion solution decreased inorganic phosphate excretion significantly (P<0.001) to 11.2±3.6% (presumably by inhibiting parathyroid gland activity), while sodium excretion was unchanged (13.5±1.1%). Parathyroidectomized rats were infused with isotonic saline at 0.50 ml/min to achieve a similar extent of extracellular fluid volume expansion as in the normal rats. In these animals inorganic phosphate excretion was as low as 0.9±0.9% of filtered phosphate, while sodium excretion was 11.8±2.2% of filtered sodium. Administration of parathormone to volume expanded parathyroidectomized rats resulted in marked increases or inorganic phosphate excretion to 41.5±3.1% of filtered phosphate (P<0.001), while sodium excretion remained unaltered (12.0±2.8% of filtered sodium), thus resembling very closely the results in normal volume expanded rats.From these results it is concluded, that saline induced phosphaturia in normal rats is mediated primarily by parathormone. Furthermore, sodium excretion during volume expansion of extracellular fluid appears to be independent of inorganic phosphate excretion and independent of changes in parathyroid activity.This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft.     

Exposition au Styrène. I. Etude expérimentale de l'absorption et de l'excrétion pulmonaires sur des sujets humains

Summary Volunteers were exposed in a controlled environment chamber at different concentrations of styrene in order to determine the quantity and percentage of the solvent absorbed and eliminated by the lungs. As a result of these experiments, it was found that the absorption rate of styrene is constant during the exposure at a level representing 88,7 ± 3,4 % of the inspired concentration. The proportion of solvent eliminated by the lungs was only of 2,62 ± 0,85 % of the absorbed dose, while the rate of decay of alveolar concentration curves with respect to time is independent of the steady inspired concentration during exposure. Accordingly, breath decay curves can be used as a method to monitor time weighted average exposure.

     

The adaptation of renal urea excretion after unilateral nephrectomy and after overloading with urea

Summary Urea and inulin clearances were measured in unanesthetized rats 5 and 50 h, and 2–3 weeks after unilateral nephrectomy. At identical i-v infusion rates, urine flow in the uninephrectomized animals was similar to that of sham-operated controls. In the low range of urine flow rates, fractional urea excretion was higher in recently uninephrectomized animals than in controls. The increase appeared to be the consequence of the increased fractional excretion of water. At higher rates of urine flow, and after large loads of urea, the single kidney excreted urea in a manner similar to that of control kidneys. Urea clearances were, in 148/150 clearance determinations, lower than the simultaneously measured inulin clearances. A large increase of GFR was observed in rats chronically loaded and acutely infused with urea.Supported by Fonds National Suisse de la Recherche Scientifique, Grant No. 3440.70.     

Urinary excretion of perphenazine and its sulfoxide during administration in oral and long-acting injectable form

Urinary excretion of the unchanged drug and perphenazine-sulfoxide was measured in a group of patients receiving at first oral perphenazine (24 mg dd) and after some weeks perphenazine-enanthate, a long-acting injectable preparation (100 mg per 14 days). A significant decrease in the absolute quantities of unchanged perphenazine and of the sulfoxide was observed. There was no constant ratio between the quantities excreted. A relative increase in the excretion, expressed in percentages of the administrated dose, was demonstrated.The author wishes to express his gratitude to W. De Waard, psychiatrist, who supervised the clinical trial in this Hospital, for his cooperation and Miss M. Potman, Mr. R. Van Elk and Mr. A. Van de Weerthof for their technical assistance.     

Demethylation and cleavage of glycosidic bonds of 4‴-methyldigoxin in man

Summary In man the oral or intravenous administration of 4-methyldigoxin yields metabolites in urine which are soluble either in chloroform or in water. The chromatographic analysis reveals demethylation as the main metabolic reaction in man. In addition to methyldigoxin and digoxin small amounts of digoxigenin-bisdigitoxoside and digoxigenin-mono-digitoxoside can be detected. The water soluble metabolites represent 7% of the radioactivity excreted in 7 days reaching a maximum within the first 8 h.     

Distribution of quaternary ammonium compounds between particulate and soluble constituents of rat liver,in relation to their transport from plasma into bile

Summary The intracellular distribution of the monoquaternary amine procainamide ethobromide (P.A.E.B.) and the bisquaternary ammonium compound d-tubocurarine was studied in the rat liver. The method described allows the concentration of free drugs in the cytosol of liver cells to be estimated. It requires homogenisation, ultra-centrifugation and dialysis techniques. Considerable differences in the subcellular distribution of the two type of agents were revealed.Unchanged and conjugated P.A.E.B. were highly concentrated in cytosol while smaller amounts were found in the particulate fraction. Binding to plasma-proteins and high molecular weight substances in the cytosol was negligible. These data point to distinct concentration gradients between cytosol and plasma and between bile and cytosol, suggesting that concentration from plasma into bile occurs in at least two steps.Cytosol concentrations of d-tubocurarine were calculated to be low while a large part is confined to the particulate fraction of the homogenate. About 50% of the d-tubocurarine found in plasma was bound to plasma-proteins. Concentration gradients between cytosol and plasma were less than unity while bile-cytosol gradients exceeded 100. K-Strophantoside, which inhibits transport from plasma into bile of d-tubocurarine but not of P.A.E.B., decreased the concentration of d-tubocurarine in bile and particulate fraction but increased that in cytosol suggesting that the inhibitory action of the cardiac glycoside is situated distal to the plasma-cytosol barrier.