Biomedical subjects
Publications and source records attributed to J G Wagner.
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An extensive survey of radioimmunoassay calibration data for prednisolone, prednisone and digoxin indicated that the common practice of preparing calibration curves with individual subject's pre-dose plasma or serum, and using this to estimate unknown concentrations for the same subject, is not supported by statistical considerations. Preparation of calibration plots from pooled data is better because this introduces less bias in estimated concentrations. Such a method also saves a great deal of time, since it is not necessary to repeat the calibration procedure each time, "unknowns" are being assayed. The data suggest that there is no optimum calibration plot for all radioimmunoassays. Rather, each antibody-drug combination should be investigated thoroughly to determine the best calibration plot for the particular combination. We found that the best calibration plots are: the logistic-logarithmic plot for prednisolone; nonlinear least squares fit to a polyexponential equation for nisolone; nonlinear least squares fit to a polyexponential equation for prednisone; and a weighted least squares regression of normalized % bound versus concentration for figoxin. The error in the radioimmunoassay is usually concentration-dependent, and, in certain regions of the standard curve, is larger than the literature indicates, since, frequently, the error has been gauged from % bound values, but should be guaged from inversely-estimated concentrations.
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Pharmacokinetic parameters were determined after a single intramuscular injection of 7.5 mg of amikacin/kg to 10 volunteers with impaired renal function (creatinine clearance rate, 2.2-65ml/min per 1.73 m2) and to six volunteers with normal renal function. The mean peak concentrations of amikacin in sera of the two groups did not differ significantly from each other and exceeded by two to five times the reported in vitro minimal inhibitory concentrations for the majority of Pseudomonas aeruginosa and Enterobacteriaceae strains. There was a significant linear relation between the elimination rate constant of amikacin and the rate of creatinine clearance; there was a significant nonlinear relation between the half-life of amikacin and the serum creatinine concentration. Knowledge of these relations may aid in adjustment of the dosage of amikacin in patients with impaired renal function, especially when such information is used in conjunction with serum assays of amikacin.
The concomitant ingestion of various foods with alcohol resulted in a decreased area under the blood alcohol concentration curve, a lower peak concentration and an increased time to reach peak. Michaelis-Menten kinetics indicated a decreased alcohol metabolism rate after the ingestion of carbohydrates or fats.
A novel method for detecting and quantitating pharmacokinetic drug-drug interactions is described. The method involves perturbation of an existing steady-state whole blood (or plasma) concentration of one drug by the other drug. The method would allow differentiation of "pharmacokinetic" drug interactions from "pharmacologic" interactions. It is shown that a bolus intravenous injection of propranolol reduced a steady-state arterial blood concentration of ethyl alcohol by 26% in the cat.
The time courses of capillary and venous blood concentrations of ethanol after oral administration of 0.30 and 0.34 g/kg doses of ethanol to two normal human subjects indicated that, by interpolation, equal capillary and venous concentrations are reached at only one time, and this time varied with the subject. The capillary/venous blood concentration ratios varied markedly as a function of time in both subjects over the entire observation period of 4 h.
Forty-five ml of 95% alcohol, diluted to 150 ml with orange juice, was taken orally by six adult male volunteers under the following conditions: A (fasting), B (following a light breakfast), C (following a heavy breakfast), D (following a steak meal), E (alcohol 1 hr after a heavy breakfast), and F (alcohol 1 hr before a heavy breakfast). Using treatment A as a reference, the average area under the blood alcohol, time curve was reduced by 36, 63, 55, 56, and 18% for treatment B through F, respectively. The reduction in area is attributed to two factors: (a) food reduced the efficiency of absorption of alcohol; and (b) food reduced the rate of absorption of alcohol, which, coupled with the operation of Michaelis-Menten elimination kinetics, contributed to the reduction in area. The latter effect is a result of changes in the ratio: instantaneous rate of metabolism/amount of alcohol in the body, which results in a smaller area when the rate of absorption is slow than when the rate of absorption is rapid. Using treatment A as a reference, the ratio of the average peak alcohol concentrations were: 1.0, 0.72, 0.35, 0.50, 0.49 and 1.11 for treatments A through F, respectively.
Bioavailability is defined and types of bioavailability studies are classified. The point is made that the validity or interpretation of comparative bioavailability data does not rest on any correlation between pharmacological or clinical response and blood levels of the drug. Equations used to assess the "first pass" effect, absolute absorption efficiency and relative absorption efficiencies are given. Methods for assessing intrinsic and relative rates of absorption are discussed. Various pitfalls in bioavailability assessment and some of the problems in interpreting bioavailability data are discussed.
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A three-way crossover bioavailability study was performed using nine adult male volunteers with three different commercial prednisone tablets. Plasma samples were assayed for prednisolone, the active metabolite of prednisone, by a radioimmunoassay method. Statistical analysis showed significant differences in the rate of appearance of prednisolone in plasma but not in the amount converted to prednisolone. The results suggest that differences in in vivo rates of appearance of prednisolone in plasma correlate with in vitro rates of dissolution.
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The Loo-Reigelman absorption method provides the correct A infinity/V1 value and the correct rate constant ka (if absorption is first order), whether metabolism occurs in compartment 1 only, compartment 2 only, or both compartments 1 and 2 of the two-compartment open models. In cases where there is metabolism in compartment 2, the disposition parameters estimated from intravenous data are only apparent and not the real values. The correct A infinity/V1 and ka values are obtained, however, only under conditions not hithertofore specified. Thes conditions are that there must be essentially no bias in the disposition parameters k12, k21 and kel, and in the C0 value estimated from the intravenous data, and that in the oral study a large number of interpolated plasma concentrations, as well as the observed plasma concentrations, must be used, especially for drugs with long half-lives. It is shown that application of the Guggenheim method to the initial At/V1, t values frequently provides a better method of estimating A infinity/V1 and ka than the classical method. If biased disposition parameters are used in application of the Loo-Reigelman method oral data, then essentially the correct ovalue of ka will be estimated, but the estimate of A infinity/V1 will be approximately equal to the true value of A infinity/V1 multiplied by the ratio of the biased C0 value (obtained in fitting the intravenous data) to the true C0 value of the intravenous data. The above indicates that intravenous data should be fitted by computer until there are no systematic deviations or trends and as small a sum of squared deviations as possible is obtainedmthe oral data should be fitted by spline or Akima methods, or similar procedures, to produce a function which passes through each observed plasma concentration and at the same time provides a large number of interpolated concentration data.
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