Biomedical subjects
Publications and source records attributed to J G Wagner.
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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.
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.
All drugs are not created equal even if the pharmacopoeia seems to suggest they are. Factors that affect bioavailability among drugs of the same type (especially oral drugs) include not only disintegration and absorption rates but also the amount of food taken before or with the dose, interactions with other drugs, the physical state of the patient, and the "first-pass effect" upon drug with high liver clearance.
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.
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.
Plasma concentration-time data in man after oral dosing of the nonsteroidal antiinflammatory agent, tolmetin sodium, were fitted to both linear and nonlinear pharmacokinetic equations. The apparent elimination half-life of tolmetin is shown to be 4.5 to 6.0 hours. An analytical method is presented which allows measurement of plasma concentrations for at least 32 hr (compared with a previous limit of about 8 hr) after a single oral dose of the equivalent of 400 mg of tolmetin acid.
A method for quantitative determination of methylprednisolone and hydrocortisone in plasma using added methylprednisolone acetate as internal standard and high pressure liquid chromatography is presented. The standard curves were evaluated statistically and logarithmic parabolic equation is preferred over the usual standard curve mathematical relationships. The method was applied to samples of one subject's plasma containing methylprednisolone and endogenous hydrocortisone after oral dosing with multiple doses of methylprednisolone.
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 postinfusion. 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 x hr)] and Km[0.0821 mg/ml] obtained fron 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 (gm/kg) 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.
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A new exponential stripping program, CSTRIP, has been developed. This program overcomes the problems associated with the use of previously published techniques and enables the rapid economical calculation of initial polyexponential parameter estimates. Values for the coefficients and exponents of the exponential terms are calculated as well as estimates of lag times. An exhaustive search procedure ensures that the results are comparable to, or better than, those obtained by manual residual methods.
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A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Clp is the plasma clearance, Vf is the "true" volume of distribution of free drug, beta is the apparent elimination rate constant, sigma is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, kf is the intrinsic elimination rate constant for free drug, and AoTB is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Clp = Vfsigma kf; (2) beta = f kf; and Vdext = (sigma/f) Vf. Only sigma, and not f, can be measured experimentally. Dividing Clp by sigma provides an estimate of the intrinsic clearance of free drug, Vfkf. A plot of Vdext versus sigma has an intercept equal to Vf, and the ratio of the slope/intercept is an estimate of AoTB/Aof, where Aof is the initial amount of free drug (equal to Vf times initial concentration of free drug in plasma). Thus, an estimate of AoTB may be obtained. Dividing the intrinsic clearance by Vf provides an estimate of kf. Thus, theoretically, estimates of Vf, kf, AoTB and f may be obtained. The variables are not separated when beta is plotted versus sigma, and curvature of such plots is expected; no useful information is obtained from such plots.
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