Ermelinda Sakmar

Pharmacokinetics of ethanol after oral administration in the fasting state

A nonlinear relationship between the total area under the blood ethanol concentration-time curve and the orally administered dose (mg/kg) of ethanol was observed in fasting subjects. A preliminary model, based on physiological considerations, was elaborated and shown, for the first time, to describe the entire time course of blood alcohol concentrations after four different doses of alcohol. The model could be refined by further experimentation.

Blood ethanol concentrations during and following constant‐rate intravenous infusion of alcohol

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2‐hr constant‐rate intravenous infusion of ethyl alcohol (8% V/V). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postirifusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one‐compartment open model with zero order input and Michaelis‐Menten elimination kinetics. The average Vm [0.232 mg/(ml × hr)] and Km [0.0821 mg/ml] obtained from these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration‐time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration‐time curve with increase in dose (gmlkg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (V/V) ethanol solution at the same constant rate.

Pharmacokinetics of diphenhydramine in man

Plasma levels and urinary excretion of diphenhydramine were measured after administration of three single 50-mg doses of diphenhydramine hydrochloride to two healthy male volunteers as an intravenous infusion, an oral solution, and a commercially available capsule. A large first- pass effect was evident from the data, with about 50% of the drug being metabolized by the liver before it reached the general circulation. The drug in solution given orally appeared to be fully available to the hepatoportal system, and the availability of diphenhydramine from the capsule was about 83% relative to the solution in one subject and 100% in the other subject. Cumulative amounts of unchanged diphenhydramine excreted in the urine were less than 4% of the administered dose. Both subjects went to sleep at the end of the 1-hr intravenous infusion, but were only drowsy following the oral treatments.

In Vitro andIn Vivo availability of some commercial prednisolone tablets

The in vitrodissolution rates of prednisolone from five commercially available 5- mg prednisolone tablets were determined in distilled water. The dissolution studies were repeated on the fastest- and slowest-dissolving brands using 0.01% polysorbate 80 in 0.1 NHCl as the dissolution medium. A two-way crossover bioavailability study was performed in 12 human male adult volunteers comparing the fastest- and slowest-dissolving brands. The plasma samples were assayed for prednisolone by a radioimmunoassay method. Statistical analysis of the data for the two brands showed no significant differences between average plasma levels of prednisolone at any sampling time. The results suggest that on the average the in vivorates of dissolution of the two brands were essentially the same, and in vitrodissolution in 0.01% polysorbate 80–0.1 NHCl medium was better correlated with these in vivoresults than dissolution in water.

Comparative Bioavailability: Eight Commercial Prednisone Tablets

Two four-treatment crossover bioavailability studies were performed in panels of 12 adult male volunteers with eight different commercial prednisone tablets. Plasma samples from the first study were assayed by radioimmunoassay for both prednisone and prednisolone. Plasma samples from the second study were assayed for prednisolone only. Statistical analyses of the data showed significant differences in the rate of appearance of prednisolone in plasma, but not in the amount convened to prednisolone. Some observations are made on the relationships between prednisone and prednisolone concentrations in plasma following oral administration of prednisone.

Correlation of plasma levels of digoxin in cardiac patients with dose and measures of renal function

There is a well‐established relationship between plasma concentrations of digoxin (PDCs) and therapeutic and toxic effects. The readily obtainable parameters, namely, dose, body weight, age, sex, and creatinine clearance or serum creatinine concentration, might be expected to allow accurate prediction of PDCs. We have now found that these parameters do not allow accurate prediction of PDCs in the individual patient, based on data collected in a panel of cardiac patients. Serial measurements of PDCs are therefore necessary in individual patients taking digoxin. These conclusions are based onL he following results. Forty‐eight equilibrium state PDCs were measured in 25 patients (13 males, 12 females) both under ward conditions (N = 11) and in the Clinical Research Center (N = 27). Multiple linear regression accounted for only 34% of the variance of the PDCs. Individual variables accounted for the following percentages of the total variance of the PDCs: dose, 14.3%; serum creatinine concentration, 10.9%; reciprocal of body weight, 3.1%; reciprocal of urinary excretion rate of creatinine, 0.9%; age, 0.7%, and height, 0.02%. Practically, the digoxin level (ng/ml) is equal to one fifth of the product of the μ/kg dose of digoxin and the serum creatinine concentration in mg/100 ml. Such a correlation accounts for only about one third of the variance of the PDCs; hence predicted levels have a wide confidence interval.

Bioavailability of prednisolone tablets

Two fourtreatment crossover studies were performed using 12 adult male volunteers in each with seven different commercially available prednisolone tablets. Plasma samples were assayed for prednisolone by a radioimmunoassay method. Statisacal analyses of the data, by analysis of variance for crossover design (ANOVA), showed no significant differences among the treatment averages at any of the sampling times except at 0.25 and 4 hr in one of the studies. There were also no significant differences among the treatment averages for peak plasma level, time of peak plasma level, area 0–12 hr, area 0–24 hr, and the halflife of elimination of prednisolone. We conclude that the average plasma concentrations of prednisolone are superimposable in a statistical sense and that the tablets tested are bioequivalent. Results of dissolution studies of six tablets of each of the seven lots of prednisolone tablets, using deaerated water in the spin filter apparatus, are presented.

Bioavailability of diphenylhydantoin

A four‐way crossover study was performed in 8 adult volunteers using a Latin square design with 4 groups of 2 subiects arranged in order of increasing body weight. Single 100 mg doses of diphenylhydantoin (DPH) sodium were administered as an aqueous solution (treatment A), the innovators capsule (treatment B), alld a commercially available generic capsule (treatment D). A single 300 mg dose (treatment C) was also administered as three 100 mg (innovators) capsules. DPH capsules from both manufacturers gave plasma levels that were not significantly different at any sampling time. Although DPH follOWing treatment A was absorbed more rapidly, prodUCing higher initial plasma levels than treatments B and D, the areas under the curves for the three treatments were equivalent. The area under the curve for treatment C was also three times that for treatment B. Plasma DPH concentrations were related to the reciprocal of body weight, but plasma protein binding had no effect on the observed intersubiect variance in plasma levels.

Comparative bioavailability: A new type of in vitro-in vivo correlation exemplified by prednisone

The average time to reach half-maximal plasma concentration of prednisolone and the average plasma concentrations of prednisolone at 0.5 and 1 hr obtained from three crossover bioavailability studies, involving testing of commercially available 5-mg prednisone tablets, were highly correlated (r⪖0.88) with parameters derived from in vitrotablet dissolution rates performed in the spin filter apparatus of Shah. The in vitroparameters were the times to dissolve 16% or 50% of the labeled amount of prednisone or the percent of the labeled amount of prednisone dissolved in 20 min in water at 37‡C. Such correlations may be useful in the setting of in vitrodissolution rate specifications for commencal prednisone tablets.

Pharmacokinetics of tolmetin with and without concomitant administration of antacid in man.

SummaryThe purpose of this study was to determine whether a concomitant single dose of antacid or multiple doses of antacid administered prior to, and with tolmetin, alter the pharmacokinetics of tolmetin when the drug was administered as a commercially available tablet containing tolmetin sodium. The possible effects of the antacid on plasma concentrations and urinary excretion of tolmetin and its major metabolite were evaluated following administration of: (a) tolmetin sodium alone; (b) antacid four time a day for three days prior to a single dose of tolmetin sodium, with continuation of the antacid during the day tolmetin was given; and (c) co-administration of single doses of tolmetin sodium and antacid. The twenty-four subject study was of the crossover type. There were no significant differences among treatment means for: (i) peak plasma concentrations of both tolmetin and metabolite, (ii) AUC 0–8 h and AUC 0-∞ for both tolmetin and metabolite, (iii) time to peak plasma concentration for both tolmetin and metabolite, (iv) plasma concentrations of both tolmetin and the metabolite at all sampling times (except for tolmetin at 2 h), (v) renal clearance of both tolmetin and its metabolite, and (vi) the amount of metabolite excreted in the 0–24 h urine. There were small, but significant, differences among amounts of tolmetin excreted in the 0–24 h urine. Semilogarithmic plots of both tolmetin and metabolite plasma concentrations past the peak concentrations were curved over the entire 8-h observation period; although the elimination half-life of tolmetin has been reported to be about one hour, the half-life most probably exceeds 2.6 h in most subjects. The results of this study indicate a lack of a significant drug-drug interaction between the non-steroidal anti-inflammatory agent, tolmetin sodium, and a commonly used antacid, which is a mixture of magnesium and aluminium hydroxides.