Carlos A. Dujovne

Cholestyramine and spironolactone and their combination in digitoxin elimination

The effects of oral cholestyramine 4 gm 8 times daily and spironolactone 300 mg daily, given independently and in combination, on the elimination rate of digitoxin were studied in 6 healthy subjects pretreated with 0.1 or 0.15 mg oral digitoxin daily for 30 days before each intervention. The mean pretreatment digitoxin concentrations for the group ranged from 21 ± 2.9 (SD) ng/ml to 28.5 ± 6.9 ng/ml. The mean control digitoxin half‐life (½) was reduced from 141.6 to 84.4 by treatment with cholestyramine alone. Treatment with spironolactone alone prolonged the mean digitoxin ½ to 192.2 hr. The mean digitoxin ½ after both active drugs was intermediate at 102.9 hr. Spironolactone did not fulfill the expectation from animal studies that it would enhance the clearance of digitoxin by cholestyramine. The prolongation of digitoxin elimination after spironolactone may contraindicate this drug in digitoxin intoxication.

Hepatotoxicity and surface activity of tricyclic antidepressants in vitro.

Abstract Cytotoxicity to isolated rat hepatocytes of the tricyclic antidepressants, chlorimipramine, nortriptyline, amitriptyline, imipramine, and of doxepin was determined by the leakage of cytoplasmic and lysosomal enzymes into surrounding media. The rank order of toxicity was: chlorimipramine > nortriptyline > amitriptyline > imipramine > doxepin. All tricyclic antidepressants tested lowered the surface tension of the salt solution contained in the tissue culture media. The rank order of surface activity was the same as that of hepatotoxicity in vitro. These results suggest that the differences in membrane damage produced by tricyclic antidepressants may be related to surface activity which in turn may determine the extent of adsorption onto cell membranes.

One‐year trials with halofenate, clofibrate, and placebo

The hypolipidemic as well as other laboratory and clinical effects of halofenate, clofibrate, and placebo were compared in 29 patients with type IV hyperlipoproteinemia in a double‐blind, controlled, therapeutic trial of 1 yr duration. Plasma drug levels were obtained to monitor compliance. Clofibrate and halofenate lowered serum triglycerides to a similar extent. The hypotriglyceridemic effect of halofenate was significant only when data from noncompliant patients were discarded. Only clofibrate lowered baseline levels of plasma cholesterol. Very low density lipoproteins were decreased and low density lipoproteins were increased by clofibrate but not by halofenate. Halofenate had a marked hypouricemic effect that was greater than that of clofibrate. The hypouricemic effect of halofenate and clofibrate was paralleled by a concomitant decrease in serum bilirubin. Abnormal increases in serum creatine phosphokinase were observed with both drugs primarily in patients who had abnormal initial levels.

Erythromycin Estolate vs. Erythromycin Base, Surface Excess Properties and Surface Scanning Changes in Isolated Liver Cell Systems

Chang liver cells and isolated rat hepatocytes were exposed to medium containing different concentrations of erythromycin estolate or erythromycin base for 1-5 h. Hepatotoxicity was quantitated by measuring leakage of enzymes from cells into surrounding medium and the damage to the plasma cell membrane seen under surface scanning electron microscopy. Only the cells exposed to erythromycin estolate showed significantly greater enzyme leakage than controls and appeared severely affected by cytopathic changes when observed under scanning electron microscopy.

Relationship between Surface Activity and Toxicity to Chang Liver Cultures of Tricyclic Antidepressants

Chang liver cell cultures were exposed to the tricyclic antidepressants, chlorimipramine (CIM), nortriptyline (NT), amitriptyline (AT), imipramine (IM), and dosepin (DOX). Loss of enzymes into surrounding media and cytopathic changes were used to quantitate cytotoxicity. Time- and concentration-related cytotoxic effects were evident for all drugs. The order of cytotoxic potency was CIM greater than NT greater than AT greater than IM greater than DOX. All tricyclic antidepressants tested lowered the surface tension of the salt solution contained in the tissue culture media and the order of their surface activity was identical to that of their cytotoxicity. It is postulated that the cellular toxicity induced by tricyclic antidepressants in vitro is related to a function of their surface activity.

Surface activity, cellular uptake and cytotoxicity of tricyclic psychoactive drugs in vitro

Abstract Isolated rat hepatocytes and Chang liver cell cultures were used to determine the relationship between magnitude of uptake by cells and cytotoxic effects of the tricyclic drugs amitriptyline (AT), imipramine (IM) and chlorpromazine (CPZ). Cell injury was evaluated by the extent of leakage of cytoplasmic and lysosomal enzymes from cells to surrounding medium and by cytopathic changes seen under surface scanning electron microscopy after drug exposure. The order of toxicity and of increasing amounts of drug uptake by cells was identical: CPZ > AT > IM. At equimolar concentrations in the medium, the uptake of CPZ by rat hepatocytes or Chang cells was 5- to 10-fold greater than that of AT or IM. Surface activity of drugs was determined to calculate their surface excess. The rank order of the surface excess of the drugs correlated with the rank order of their degree of uptake by the cells suggesting that surface active properties could play a role in differences in bioavailability and toxicity of these drugs to liver cell membranes.

Liver cell culture toxicity of general anesthetics

Abstract Chang liver cells in monolayer tissue cultures were exposed to various concentrations of ether (E), isoflurane (IF), halothane (H), or methoxyflurane (MF) for 5 hr. Loss of intracellular enzymes into surrounding media was used to quantitate cytotoxic effects. Drug concentrations in cells and media were monitored during the experiments. Dose and concentration-related cytotoxic effects were evident for all drugs. The order of cytotoxic potency was MF > H > IF > E; the differences among them were statistically significant. The in vitro effects on liver cells seem to correlate with the knowledge on comparative hepatotoxic potentials of these drugs in man and suggest that an additional direct, dose-related toxic effect on hepatocellular membranes may play a role in the seemingly hypersensitivity-type of hepatotoxic reactions to halogenated anesthetics.

Chlorpromazine Uptake by Isolated Rat Hepatocytes

Summary Isolated rat hepatocytes were found to adsorb (nonspecific binding) as well as to absorb chlorpromazine. The linearity of chlorpromazine adsorption was dependent on the drug concentration in the incubation medium. Also, the absorption of chlorpromazine was linear with respect to the drug concentration, suggesting an unsaturable uptake process which was considered to represent simple diffusion, with a diffusion coefficient of 0.15 nmole chlorpromazine/mg protein/min/μM. Chlorpromazine uptake was not inhibited by the action of a series of metabolic inhibitors present in the reaction medium. The drug is rapidly and to a large extent adsorbed onto hepatocellular membranes.

The interaction between halofenate and propranolol

The effect of halofenate on beta adrenergic blockade by propranolol was studied in 4 subjects during chronic drug administration in a randomized, double‐blind study. The plasma propranolol concentration was significantly lower during treatment with halofenate than with placebo. The reduction in propranolol levels correlated with a decrease in beta adrenergic blockade. The mechanism for the decrease in plasma concentration has not been determined.

Hepatotoxicity of general anesthetics on rat hepatoma cells in culture.

Summary Rat liver hepatoma cells in monolayer tissue cultures were exposed to various concentrations of ether (E), isoflur-ane (IF), halothane (H), or methoxyflurane (MF) for 5 hr. Loss of intracellular enzymes into surrounding media was used to quanti-tate cytotoxic effects. Drug concentrations in cells and media were monitored during some of the experiments. Dose- and concentration-related cytotoxic effects were evident for all drugs. The order of cytotoxic potency was MF > H > IF > E. The differences were not related to the intracellular concentrations accomplished by each drug. The direct dose-related toxic effects of MF and H on the cell membranes suggest that other than hypersensitivity factors may play a role in the hepatotoxicity from these halo-genated anesthetics. The correlation between the in vitro effects on liver cells and the suggested comparative hepatotoxic potentials of these drugs in man supports the possible usefulness of this method to gather additional information on comparative hepatotoxic potential of general anesthetics.