Em Sellers

Interaction of chloral hydrate and ethanol in man: I. Metabolism

The interaction of chloral hydrate and ethanol metabolism was studied in 5 normal male volunteers. Compared to chloral hydrate alone, ingestion of ethanol30 minutes after chloral hydrate results in significantly higher and more prolonged concentrations of plasma trichloroethanol and in lower plasma trichloroacetic acid levels and urinary trichloroethanol glucuronide. Chloral hydrate ingestion in turn affects ethanol metabolism and causes peak blood ethanol concentrations to be reached earlier and to be higher than after ethanol alone. Accompanying the higher blood ethttnollevels are lower blood acetaldehyde concentrations. Blood ethanol concentration one‐half hour after ethanol ingestion is linearly related to the plasma trichloroethanollevel at the time of ethanol ingestion. In vitro studies on the mechanism of these metabolic interactions showed that the elevated blood ethanol concentrations are due to competitive inhibition of alcohol dehydrogenase by trichloroethanol (Ki = 8. 7 × 10−5M). Ethanol stimulates NADH production and thereby increases the rate of chloral hydrate reduction to trichloroethanol by liver alcohol dehydrogenase. Human red blood cells also reduce chloral hydrate to trichloroethanol (Km 4.0 × 1D−4M, Vmax, = 3.6 p,m per minute per cubic centimeter RBC).

Diazepam actions and plasma concentrations following ethanol ingestion

SummaryIn eight normal volunteers, the combination of ethanol (0.5 g/kg) and diazepam (10 mg) administered orally produced a greater decrease in motor performance on a pursuit rotor than diazepam alone. The pharmacologic effect of diazepam was enhanced by 73% and this potentiation was associated with significantly greater diazepam concentrations (p<0.01) than after diazepam alone. The failure to observe any increase in the concentrations of the principal metabolite, N-desmethyl diazepam, during the period of enhanced pharmacologic effect precludes any change in the demethylating metabolic process as being responsible. The data suggest (0.10>p>0.05) a trend to a smaller volume of distribution of diazepam when ethanol is administered prior to diazepam ingestion. The subjects showed acute tolerance to the effects of diazepam. Lower plasma concentrations on the ascending side of the plasma diazepam concentration versus time profile were linked with the same pharmacologic responses associated with a greater drug concentration on the descending portion, of the same curve.

Interaction of warfarin stereoisomers with human albumin

Edward M. Sellers,2M.D. , Ph.D., Jan Koch-Weser, M.D. Clinical Institute, Addiction Research Foundation, Toronto, and Departments of Medicine and Pharmacology, Harvard Medical School and the Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Mass., U.S.A. Received 5 May 1975 In the ra?? S(-) warfarin has approximately six times the hypoprothrombinemic acticity of R(+) warfarin. (Breckenridge and Orme, 1972). In man S(-) warfarin is 3.4 times more potent than R(+) warfarin. (OReilly 1969, OReilly 1974). One simple explanation of this difference in potency would be a lesser degree of S isomer binding to human albumin with higher free concentrations of S available at the site of action. A precedent for differences in isomer binding exists. (Karush 1952). Rat-warfarin is highly bound to human albumin. (OReilly 1967, 1969). Results of previous binding studies did not resolve the question of whether there is a difference in the isomer binding of warfarin to human albumin since the results were obtained at pH 10.0 and 27C and no statistical analysis was applied. (Oleilly 1969, OReilly 1971). An unexplained aspect of the results was that the calculated standard free energies (&Fe,) for the R (-7.28 kcal/mole) and S (-7.39 kcal/mole) isomers were lower than reported for the racpreparation (-7.16 kcal/mole) (OReilly 1969). Our experiments were performed to determine if there are differences in R and S isomers binding and indicate that the binding of S(-) warfain to human album is significantly greater than for the R(+) isomer.

Interaction of disulfiram with benzodiazepines

The disposition of chlordiazepoxide (50 mg, intravenously), diazepam (0.143 mg/kg, orally), and oxazepam (0.429 mg/kg, orally) were studied in normal and alcoholic men before and after chronic disulfiram administration. Decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05), diazepam (41%, p < 0.05), and their active N‐desmethyl metabolites were observed. Oxazepam has no important active metabolites and its net disposition is minimally altered by disulfiram. Oxazepam disposition is unaffected by age and liver disease. These considerations together with that of the short half‐life of oxazepam (median, 6.1 hr) suggest that oxazepam may be the drug of choice if benzodiazepine therapy is used for patients taking disulfiram.

Interaction of chloral hydrate and ethanol in man: II. Hemodynamics and performance

Changes in heart rate, arterial pressure, and skin temperature and in performance tests were studied in 5 male volunteers after ingestion of placebo, ethanol, chloral hydrate, both drugs, or ethanol after 7 days of chloral hydrate pretreatment. Ethanol ingestion was always associated with an increase in heart rate at 0.5 and 1.0 hours; this tachycardia was enhanced by pretreatment with chloral hydrate. Chloral hydrate followed by ethanol also caused greater increases in skin temperatures than other treatments. In one subiect this sequence led to a marked vasodilation reaction characterized by flushing, palpitations, and headache. At the peak of the reaction the blood acetaldehyde level was only half that after ethanol alone which had caused no reaction. The ability to perform a complex motor task was poorest when chloral hydrate was taken with ethanol. Auditory vigilance was significantly impaired by ethanol; concurrent chloral hydrate treatment further decreased performance. The “knock‐out” drop effect was not seen.

INFLUENCE OF INTRAVENOUS INJECTION RATE ON PROTEIN BINDING AND VASCULAR ACTIVITY OF DIAZOXIDE

The binding of a drug to plasma proteins affects its activity, distribution, and rate of metabolism and glomerular filtration. The amount of drug bound is dependent on the protein concentration, the number of binding sites, the affinity of each binding site for the drug, and the free drug concentration. Alterations in any one of these factors change the fraction of drug in the free form. A decrease in protein concentration or binding capacity or displacement of a bound drug by other drugs or drug metabolites increases the free drug concentration. This increase enhances the pharmacologic effect and increases the rate of elimination of the bound drug.* After rapid intravenous injection of a drug, its serum concentration in some parts of the circulatory system is far higher than after mixing with the circulating blood volume and extravascular distribution have been completed. The clinical effect of such transiently high drug concentrations depends on the rate of blood flow to the organ on which the drug acts, the accessibility of the drug receptors, and the rapidity of onset of the response. Thus, the rate of intravenous injection may be critically important in determining the therapeutic or toxic effects of drugs that act at the surface of cells in the cardiovascular or central nervous systems, but unimportant for slowly occurring responses within cells located in less perfused tissues. If the injected drug is highly bound to a plasma protein, the rate of injection assumes additional importance. During the initial mixing and distribution phases, the binding capacity for such a drug on the protein present in the blood volume that contains the drug can be exceeded. Compared to steady-state concentrations after mixing, extremely high free drug concentrations can thereby be achieved in some of the circulating blood for brief periods after rapid intravenous injection. Diazoxide is a highly protein-bound drug that produces its maximum therapeutic effect only when given by intravenous This paper shows the importance of the protein binding of diazoxide for its activity and elimination and discusses the influence of the intravenous injection rate of the drug on its concentration at the arteriolar site of action.

Binding of diazoxide and other benzothiadiazines to human albumin

Abstract The binding of seven benzothiadiazines to human albumin was studied by equilibrium dialysis. All these 1,2,4-benzothiadiazine-1,1-dioxide analogs are highly bound to human albumin. The unsubstituted benzothiadiazine nucleus is bound less than the substituted analogs. Addition of a chlorine at C-6 and C-7 markedly increases binding, but further addition of methyl or sulfamyl groups results in some reduction of binding. Binding studies on benzothiadiazines do not demonstrated independent binding sites on albumin. Binding of drugs to albumin can be evaluated by fitting a logistic function to the experimental points with a least squares method. This empirical, objective technique allows examination of the nature of the bonds between drug and protein. Diazoxide, the 7-chloro-3-methyl analog, was used for detailed investigations into the mechanism of protein binding of the benzothiadizines. The effects of pH, temperature, ionic strength, cations and deuterium on the binding of diazoxide to human albumin indicate that the drug is bound mainly by hydrophobic interaction and to a lesser extent by hydrogen bonding. Difference spectroscopy studies show a shift in the electron distribution of diazoxide with binding.

Disposition of intravenous diazepam in young men and women

SummaryThe disposition of a single intravenous dose of diazepam (10 mg) was studied in 11 young, healthy subjects (6 males and 5 females on oral contraceptives). Plasma samples were obtained over 28 days and diazepam and N-desmethyldiazepam plasma concentrations and diazepam free fractions were determined. The salivary excretion of diazepam and N-desmethyldiazepam was studied over 72 h. A series of psychomotor performance tests were administered over the first 8 h. Interindividual variation in mean diazepam disposition over time is not principally related to variation in plasma protein binding; 93% of the variation in clearance is accounted for by variation in intrinsic clearance. Interindividual variation in diazepam disposition is modest but the plasma clearance of diazepam in women on oral contraceptives (median 14.0 ml/min) is significantly (p=0.004) less than in men (median 23.4 ml/min) and the area under the curve (AUC) of diazepam is highly correlated with the AUC of the principal active metabolite (r=0.90, p<0.001). The AUC of N-desmethyldiazepam (median 9.2 µg·h/ml) in women is greater (p=0.06) than in men (median 7.5 µg·h/ml). On chronic administration of diazepam, therefore, women taking oral contraceptives will have greater plasma concentrations per unit dose of both diazepam and N-desmethyldiazepam than men. The clearance of diazepam in control groups of 11 young men (median 23.8 ml/min) and 10 young women not taking oral contraceptives (median 26.8 ml/min) is not significantly different. Plasma and salivary concentratrions of diazepam are correlated (p<0.001) but the predictive value of this correlation is limited (r=0.70) since the ratio of salivary to plasma concentrations varies significantly over the day. The use of calculated free diazepam plasma concentrations does not improve the correlation (r=0.68) but the slope of this regression (1.00) is that predicted by theory.

Survival after massive procainamide ingestion

A 79 year old man with coronary heart disease and renal insufficiency ingested approximately 19 g of procainamide hydrochloride. The plasma procainamide concentration peaked at 77 mg/liter 3 hours after ingestion. Despite severe hypotension, intraventricular conduction disturbances and central nervous system depression, the patient survived with supportive care. The serum half-life of procainamide was 8.8 hours throughout the first 24 hours. Renal clearance of procainamide was similar to creatinine clearance, but biotransformation was most important in the elimination of the drug. Peritoneal dialysis contributed little to the removal of procainamide.

Enhancement of warfarin‐induced hypoprothrombinemia by triclofos

Daily administration of hypnotic doses of triclofos (trichloroethyl sodium phosphate) significantly prolonged prothrombin time in 7 volunteers chronically anticoagulated with warfarin. Mean sensitivity to warfarin (prothrombin time prolongation/cumulative 72 hour warfarin dose) increased by 49 per cent during the first week of triclofos therapy. Plasma concentrations of factors II and X fell within 9 hours of a single dose of triclofos. A metabolite of triclofos, trichloroacetic acid, accumulated in plasma to 80 µg per milliliter during one week of triclofos administration. The displacement of warfarin from human albumin by trichloroacetic acid can account for the potentiation of warfarin action by triclofos.