High performance liquid chromatographic determination of methapyrilene hydrochloride in feed and sleep aid tablets.

Methapyrilene hydrochloride (MP-HCl) was extracted from feed with methanol and determined by reverse phase partition chromatography in less than 15 min, using isocratic elution with acetonitrile-1.1% ammonium carbonate (1 + 1) as the mobile phase. This procedure was tested on feed treated with MP-HCl at levels of 125, 500, and 2000 ppm. Recoveries were 104, 95, and 96% with coefficients of variation of 2.4, 1.6, and 0.6%, respectively. MP-HCl in feed was stable for 14 days. This method was also successfully used to determine MP-HCl in 3 sleep aid tablets.

Comparison of the in vitro and in vivo release of digoxin from four different soft gelatin capsule formulations.

A blinded, four-treatment crossover study in 16 normal adult male volunteers compared plasma concentrations and urinary excretion of digoxin, measured by radioimmunoassay, after oral administration of soft gelatin capsule formulations of digoxin. Four 0.4-mg formulations with different in vitro "burst times" and dissolution rates were administered, with 2-week intervals between treatments. The two capsules with lowest in vitro burst times (2.9 and 16 min) gave comparable in vivo results. The other two capsules, with in vitro burst times of 62 and 229 min, produced significant delays in digoxin absorption. In vitro-in vivo correlations were obtained by comparing the logarithm of the in vitro burst time with time to peak plasma level and the time to the first measurable plasma level (> or = 0. 05 ng/ml). Also, the mean time to peak plasma level correlated with the logarithm of the time required to release either 50% or 85% of the digoxin in vitro. No significant changes were found in the amount of digoxin absorbed from each capsule as determined by urinary excretion or AUC0-infinity.

Influence of kaolin--pectin suspension on digoxin bioavailability.

The effect of a kaolin--pectin suspension on the bioavailability of orally administered digoxin was evaluated when both drugs were given concomitantly and when their time of administration was separated by 2 hr. Coadministration of the antidiarrheal with the cardiac glycoside delayed absorption of the latter and, at the same time, decreased by 62% the amount of drug absorbed. Intersubject variation in digoxin bioavailability also was increased more than twofold. When the kaolin--pectin suspension was given 2 hr before the cardiac glycoside, the digoxin absorption rate was not affected, although its relative extent of absorption was reduced by about 20%. In contrast, when the antidiarrheal was given 2 hr after digoxin, neither the rate nor the extent of absorption of the cardiac glycoside was perturbed. No change in the intersubject variability in digoxin bioavailability was noted whether the antidiarrheal was given 2 hr before or 2 hr after the cardiac glycoside.

Sensitive radioimmunoassay for digoxin in plasma and urine.

A reproducible and sensitive radioimmunoassay for digoxin in either serum, plasma or urine is described. Using 0.5 ml of serum or plasma, the assay sensitivity is 0.05 ng of digoxin/ml. The antiserum and tracer solutions employed are available in a kit sold in the United States. All other reagents were prepared in the laboratory. The assay allows measurement of digoxin in plasma or serum for 96 hours after single 0.5 mg doses of digoxin; this is necessary in human bioavailability studies to accurately estimate the total area under the digoxin concentration, time curve from zero to infinite time. In contrast, with the kit assay, employing 0.2 ml of plasma or serum, it has been reported that the 12 hr serum digoxin levels, after single 0.5 mg doses, are, in most subjects, below the sensitivity limit (about 0.5 ng/ml) of the assay.

Plasma prednisolone concentrations: comparison of radioimmunoassay and competitive protein binding assay.

A comparison was made between plasma concentrations of prednisolone measured by both competitive protein binding radioassay (CPB) and radioimmunoassay (RIA) and, with each assay, using a calibration curve generated from individual subject data and from pooling the individual calibration curva data. The plasma samples were obtained from six normal adult male volunteers who were pretreated with dexamethasone to suppress endogenous hydrocortisone and who then ingested 10 mg of prednisolone. Both the standard curve data and the plasma concentrations were evaluated statistically. It was shown that the CPB method has considerably greater precision than the RIA method and could be employed in bioavailability and pharmacokinetic studies of both prednisolone and prednisone. It was also shown that corticosteroid binding globulin cross-reacts considerably less with the major metabolite of prednisolone, 20beta-dihydroprednisolone, than the particular antiserum used in the RIA.

High-pressure liquid chromatographic (HPLC) determination of tolmetin and its major metabolite in plasma.

A high-pressure liquid chromatographic assay was developed for the quantitative determination of tolmetin and its major metabolite in plasma. Determination of tolmetin was compared to a previously reported spectro-photometric assay method. The standard curves were evaluated statistically and daily standard curves were preferred over a pooled standard curve. The method was applied to samples of one subject's plasma containing both tolmetin and its major metabolite.

Pharmacokinetics of peniobarbital in the cat and comparisons with the rabbit and man.

In eight experiments involving four cats, doses of 12.5 to 50 mg of sodium pentobarbital per kg of body weight were administered intravenously and pentobarbital plasma concentrations (from arterial blood) were measured as a function of time. Pharmacokinetic linearity was evidenced by a mean plasma clearance (C1p) of 1.81 ml/(kg x min), with a coefficient of variation of 16.6%, and a range of 1.51 to 2.36 for all experiments, and, a linear relationship between total area under the curve (AUC) and mg/kg dose in cat "4 given doses of 12.5, 25 and 50 mg/kg. However, the apparent elimination half-life, (t1/2)beta' averaged 4.87 hr, with a coefficient of variation of 40.7%, and range of 1.80 to 7.52 in all experiments, and, in cat "4 the half-life was the same, namely 7.5 hr following the two higher doses, but lower, namely 4.7 hr, after the lowest dose. There was also evidence of kinetic nonlinearity in the intial fall-off portions of some of the curves. Results are compared with literature data for both rabbits anamen. The order of plasma clearances in units of ml/(kg x min) were: rabbit greater than cat greater than man. For neither the rabbit nor the cat were there any significant correlations between calculated pharmacokinetic parameters and mg/kg doses using data from all animals studied; this also suggests kinetic linearity.

Effect of food on the bioavailability of prednisone.

Two commercial prednisone tablets were studied which had previously been shown by Sullivan et al.5,6 to have the slowest and fastest in vitro rates of dissolution, and the slowest and fastest rise to peak plasma prednisolone concentrations in human beings. The effect of food on the adsorption of these two tablets was studied in a crossover study, which also repeated the fasting conditions used by Sullivan et al.6 Marked differences in mean prednisolone plasma concentrations during the 0- to 2-hour absorption phase were observed between the two tablets again, but food did not affect either tablet with respect to mean plasma prednisolone concentrations.