Choleresis and hepatic transport mechanisms

Summary To investigate binding of drugs to biliary micelles as a possible factor in the hepatic transport process, interaction of two uncharged compounds, ³H-ouabain and ³H-K-strophanthoside with biliary micelles was studied by ultracentrifugation of bile. The various bile acids normally present in rat bile were predominantly associated with cholesterol containing micelles, but not to the same extent. The tendency of the bile salts to be associated with mixed micelles was the greatest for conjugated chenodeoxycholate, somewhat lower for conjugated deoxycholate and the least for conjugated cholate. The sedimentation patterns of the water-soluble cardiac glycosides, added in vitro, indicated binding to mixed biliary micelles as well as non-cholesterol containing micelles. Also mannitol, a drug used to estimate canalicular bile flow, was found to be associated with both categories of biliary micelles.In spite of the binding of cardiac glycosides to the micelles, administration of taurocholate, which promotes formation of biliary micelles, did not stimulate biliary output of both glycosides. Also administration of the choleretics dehydrocholate and ethacrynic acid failed to enhance biliary output of the glycosides.These results indicate, that binding of drugs to biliary micelles diminishes the free concentration of drugs in bile and confirms earlier studies with organic anions that binding to biliary micelles is not a pertinent factor in the rate of biliary excretion.     

Disposition of valproic acid in man

Summary The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9±2.6 h in the single dose and 17.3±3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064±0.0011 l/kg×h. The apparent volume of distribution was small at 0.15±0.2 l/kg. The mean steady state plasma concentration (C_ss) reached after 4 days was 81.3±13.0 µg/ml. C_ss observed was lower than C_ss predicted (99.2±14.7 µg/ml) from single dose kinetics (p<0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7±0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.Supported by Sandoz Stiftung für Therapeutische Forschung     

Acute acetylsalicylic acid poisoning: Treatment with forced alkaline diuresis and diuretics

Summary The effect of acetylsalicylic acid (ASA) in patients with renal insufficiency has been examined. In one investigation (A), in patients with a mean GFR of 23.0 ml/min the acute effects of ASA 750 mg i.v. (lysine-ASA 7.5 ml) and 0.9% NaCl 7.5 ml on renal water and solute output and on the clearance of inulin, creatinine and PAH were compared. In another (B) the effects of simultaneous administration of ASA 750 mg or 0.9% NaCl 7.5 ml i.v. with an infusion of furosemide 250 mg were investigated in six patients (mean GFR 12.9 ml/min) in a cross-over study. In study A there was a significant fall in urinary sodium excretion within the first 15 min after ASA administration, with a maximal decrease to 21% of the control period. Urine flow fell to 35%, osmolal clearance to 41%, inulin clearance to 54% and PAH clearance to 66%, whilst tubular reabsorption of sodium increased. The effect of ASA lasted for 2–6 h. The mean salicylic acid concentration during the first two hours after ASA administration was 60.0 µg/ml, and the mean protein bound salicylic acid (SA) was 70.4%. There was no effect of placebo (0.9% NaCl7.5 ml) on renal function. Pretreatment with ASA 750 mg i.v. attenuated the diuretic effect of furosemide 250 mg, and reduced creatinine clearance significantly within 0–2 h after drug administration.     

Mobilization of Methyl Mercury in Vivo and in Vitro using N–acetyl–DL–penicillamine and other Complexing Agents

Abstract The distribution and excretion of mercury was studied in mice given a single intravenous dose of 5 umol/kg of methyl mercuric chloride. Oral treatment with N–acetyl–DL–penicillamine (3 mmol/kg per day) removed more mercury from the brain and from the whole body than the corresponding treatment with other complexing agents, and it was also effective on delayed treatment. Even more mercury was removed into the faeces and the urine, by higher doses of N–acetyl–DL–penicillamine, and 4 days of treatment with 27 mmol/kg per day of this compound did not give rise to any significant toxic symptoms in the mice. In vitro experiments showed that the chemical affinity of N–acetyl–DL–penicillamine for methyl mercury was higher than that of the other thiols tested, except D–penicillamine. In contrast to the latter, N–acetyl–DL–penicillamine easily penetrated the cellular membranes, and therefore rapidly removed a substantial fraction of methyl mercury from the blood cells. It is assumed that N–acetyl–DL–penicillamine can reduce the mercury concentration in brain cells by converting the intracellularly non–diffusible methyl mercury into a freely diffusible complex.     

Pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium after oral administration to man

Summary A method has been developed for the quantitative determination of heptabarbital [5-(1-cyclohepten-1-yl)-5-ethylbarbituric acid] in human plasma after administration of single therapeutic doses of the drug. It involves a single extraction step followed by gas chromatography with alkali flame ionization detection, and the results were linear in the concentration range 0.125 – 5.0 µg/ml plasma. The pharmacokinetics and relative bioavailability of heptabarbital and heptabarbital sodium were studied in a crossover design in 7 healthy volunteers after oral administration of 20 tablets containing 200 mg heptabarbital and hard gelatine capsules containing an equivalent amount of its sodium salt. Heptabarbital concentrations in plasma were determined at regular intervals. The absorption of heptabarbital from the tablets was quite slow and peak level times varied from 1.5 to 4 h. The sodium salt was absorbed more rapidly and peak concentrations occurred between 1/3 and 2 h. In all cases the elimination of heptabarbital could be described by a single first-order process with an average half-life of 7.6 h (range 6.1 – 11.2 h). The half-life of the drug in each individual was about the same in the two trials. The relative bioavailability in each volunteer was estimated by comparing the areas under the plasma concentration curves. The sodium salt had an average bioavailability of 83% relative to the free acid. In some volunteers urinary excretion of unchanged heptabarbital was measured; cumulative excretion amounted to 0.16 – 0.30% of the administered dose. Four volunteers received one tablet each night for eight or ten days, but no accumulation was found. In three volunteers the half-life of the drug prior to and after these experiments did not change, whereas in the other volunteer the half-life decreased from 7.1 to 4.6 h. The possibility of enzyme induction should be considered when heptabarbital is taken regularly. It was concluded that heptabarbital was a suitable drug for the treatment of insomnia, since its half-life was rather short. Heptabarbital sodium may be used for induction of sleep, whereas Medomin^® tablets, i.e. heptabarbital free acid, may be prescribed when the maintenance of sleep is the primary reason for treatment with a hypnotic drug.     

The effect of mercuric chloride on the excretion of two urinary enzymes in the rat

The effect of intravenous injections of HgCl₂ on the renal excretion of alkaline phosphatase (AP) and leucine aminopeptidase (LAP) was investigated in rats. On the first day after Hg enzyme excretion showed a linear rise with the Hg dose from a threshold value of 0.44 mg Hg/kg. On the second day a statistically significant effect was seen already after 0.25 mg Hg/kg. After doses of 0.75 mg/kg or more a decrease of enzyme activity below control values occurred which persisted for more than 4 days.Treatment with 2,3-dimercaptopropansulfonate (DMPS) brought about a normalization of AP excretion. An effect on LAP excretion was observed only with early treatment. The same holds for the effect of DMPS on Hg-induced lethality.The usefulness of a measurement of LAP excretion for estimating the exposure to inorganic mercury is discussed.

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Zusammenfassung Die Wirkung von intravenös verabreichtem HgCl₂ auf die renale Ausscheidung von alkalischer Phosphatase (AP) und Leucinaminopeptidase (LAP) wurde an Ratten untersucht. Am ersten Tag nach Hg-Injektion erfolgte ein Anstieg der Enzymausscheidung, der von einem Schwellenwert von 0.44 mg Hg/kg ausgehend eine lineare Abhängigkeit von der Hg-Dosis aufwies. Am zweiten Tag wurde ein statistisch signifikanter Effekt bereits nach 0.25 mg Hg/kg beobachtet. Nach Dosen von 0.75 mg Hg/kg oder mehr fand ein Abfall der Enzymaktivität unter die Kontrollwerte statt, der mehr als 4 Tage anhielt.Behandlung mit 2,3-Dimercaptopropansulfonat (DMPS) bewirkte eine Normalisierung der AP-Ausscheidung. Eine Wirkung auf die LAP-Exkretion wurde nur bei baldiger Verabreichung von DMPS beobachtet. Das gleiche gilt für den Effekt von DMPS auf die Hg-induzierte Letalität.Die Nützlichkeit einer LAP-Bestimmung im Urin zur Abschätzung einer Hg-Inkorporation wird diskutiert.

     

Cystinuria genotypes predicted from excretion patterns

Genotypes of 17 patients with cystinuria were predicted from data based on excretion rates of the families' obligate carriers. The methodology differed from that used by other investigators as it did not employ intestinal biopsy studies or loading dose measurements. The Type I form was more common than either Type II or Type III and frequently occurred in combination to give compound heterozygous genotypes with the Type III form.     

Renal gluconate excretion after 6-aminonicotinamide

Summary After application of 6-aminonicotinamide, an increasing amount of gluconate was found in the urine. No correlation with the renal excretion of electrolytes could be established.     

Biliary excretion of 64Cu, 65Zn and 203Hg in the rat with liver injury induced by CCl4

In rats the effect of a chronic administration of CCl₄ on the excretion and disstribution of ⁶⁴Cu, ⁶⁵Zn, and ²⁰³Hg was investigated. The biliary excretion of these metals was studied with particular attention. It was found that total excretion of ⁶⁴Cu, ⁶⁵Zn, or ²⁰³Hg from the organism did not change significantly in comparison with the control group, but the ratio of individual excretion pathways did change. The course of excretion curves regarding the bile in exposed animals is prolonged. The histologic examination of the livers revealed a large interindividual variability in the response of the liver tissue to the same CCl₄ exposure. Differences in distribution in the kidneys and livers in exposed and control animals was also found.