Plasma volume changes as a result of equilibrium dialysis.
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Dialysis↗
Biomedical subjects
J G Wagner
Publications and source records attributed to J G Wagner.
High-performance liquid chromatographic determination of ibuprofen and its major metabolites in biological fluids.
A sensitive and selective high-performance liquid-chromatographic assay for ibuprofen and its major metabolites in biological fluids is described. To ensure good chromatographic separation the drug and metabolites were run on a gradient elution system and detected with a variable wavelength detector set at 220 nm. A second, more rapid, isocratic system is also described for the detection of only ibuprofen.
Chromatography, High Pressure Liquid↗
Prediction of steady-state verapamil plasma concentrations in children and adults.
With data on adults from two previous articles it was found that the average steady-state plasma concentration of verapamil in subjects on long-term oral therapy of 80 mg every 6 hr (Y) correlated strongly with the area under the curve from zero to infinity (AUC0-x/6 (X) where the area refers to that for a single oral dose of 80 mg (Y - 2.41X, n - 15, r - 0.923, P less than 0.001). Steady-state concentrations are predictable from the single-dose data, with an average absolute deviation of 11.1%. We gave seven children (7 to 19 yr old) an initial intravenous bolus dose of 0.1 mg/kg, followed by a 20-min constant rate infusion of 0.007 mg/kg/min. Twenty-four hours after the bolus dose they were put on oral therapy (40 to 80 mg every 6 hr) and 1 mo later the minimum steady-state verapamil plasma concentration (Cminss) was measured. Plasma concentration-time data obtained after the infusion were fitted to biexponential (two sets) or triexponential equations (five sets). The coefficients of the postinfusion polyexponential equations were converted to those for the 0.1-mg/kg bolus dose alone. Mean parameters estimated were: plasma clearance 0.500 l/min, steady-state volume of distribution 279 l, V beta 394 l, half-life 9.17 hr, and mean residence time 10.0 hr. Many correlations were made between the oral Cminss values and functions obtained from the intravenous data. The best correlation was that between Cminss and the predicted steady-state concentration at 3 hr after dosing when bolus doses would be given at 6-hr intervals based on the single-dose intravenous date (r = 0.985, P less than 0.001); this correlation allowed Cminss to be predicted with an average absolute deviation of 10%. Norverapamil was measured in plasma after oral dosing, but was not detectable after intravenous dosing.
Administration, Oral↗
High-performance liquid chromatographic determination of penicillamine in whole blood, plasma, and urine.
A high-performance liquid chromatographic method for the determination of penicillamine in plasma, whole blood, and urine samples is described. The method uses a commercially available electrochemical detector at a potential of +0.1 V versus the Ag/AgCl reference electrode. This method is selective and sensitive for sulfhydryl compounds. The chromatography separates penicillamine from other endogenous sulfhydryl compounds with a limit of detection for penicillamine in biological samples of ca. 10(07) M.
Buffers↗
The assessment of the intrasubject variability in digoxin absorption in man from two oral dosage forms.
The reproducibility of drug absorption within a given subject as well as the evaluation of bioavailability of two digoxin dosage forms were studied. The data showed (a) a higher initial plasma digoxin concentration after the soft elastic gelatin (SEG) capsule; (b) a more irregular absorption after the tablet; (c) on the average, the coefficients of variation of individual plasma concentrations were lower after the capsule; and (d) for the capsule, the intrasubject variations of the peak plasma concentrations, time of peak, area under plasma concentrations-versus-time curve (AUC), and amount digoxin excreted in urine (Ae) were on the average 60 per cent of the variations in the tablet parameters. The ratios of AUC and Ae for capsule/tablet were essentially unity, indicating that the amount digoxin absorbed from the 0.4-mg digoxin SEG capsule is identical to that from a 0.5-mg standard reference tablet.
Absorption↗
Parabolic equation relating free and total drug concentrations in cases of nonlinear plasma protein binding.
In many cases of nonlinear drug-protein binding, investigators have fitted data to the classical Langmuir model with two classes of binding sites involving four parameters. For human serum albumin binding of tolmetin and salicylate, a simple two-parameter parabolic equation relating free to total concentrations fitted the binding data better. Thus, the free fraction corresponding to the serum or plasma drug concentration in the blood sample taken from a subject can be estimated directly from the parabolic model. This is not the case when the Langmuir model is used to describe nonlinear binding data since the positive root of a cubic equation must be obtained to estimate the free from the total concentration. The direct relationship between free and total drug concentrations would be useful in many clinical situations.
Blood Proteins↗
The pharmacokinetics of penicillamine in a female mongrel dog.
The pharmacokinetic parameters of D-penicillamine were investigated by administering four intravenous bolus doses, four oral doses, and six constant rate intravenous infusions to a female mongrel dog at dosages comparable to 250, 500, 750, and 1000 mg in man. The pharmacokinetics of D-penicillamine demonstrated nonlinearity in the dog. There was more than proportional increase in the area under the whole blood concentration curve for an increase in the bolus intravenous dose. The steady state whole blood, plasma, and packed cells levels of penicillamine were increased more than proportionately for an increase in the intravenous infusion rate. Total body clearance of penicillamine was decreased by increasing the dose or the infusion rate of penicillamine. Correspondingly, the estimated half-life of unchanged penicillamine in the whole blood was decreased for increased intravenous bolus doses. The renal clearance of penicillamine was nonlinear, decreasing with time during the bolus experiments and increasing at higher infusion rates. The nonrenal clearance was decreased at higher infusion rates, suggesting that a saturable nonrenal elimination process exists for penicillamine in the dog. The nonlinearities that were observed in the dog, if also present in man, may be responsible in part for the dose related side effects reported clinically for penicillamine.
Administration, Oral↗
Evidence of nonlinearity in digoxin pharmacokinetics.
Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 h, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01 greater than p greater than 0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p less than 0.001). Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics.
Biological Availability↗
History of pharmacokinetics.
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Biological Availability↗
Penicillamine kinetics in normal subjects.
The kinetic characteristics of penicillamine are reported in four fasting subjects after four oral doses each. On late test days, tow of the subjects received an additional single dose 30 min after a large breakfast. On subject originally included in the study had to drop out because of gastrointestinal disturbances following each of two single doses of penicillamine. The fasting plasma levels of penicillamine observed in this study displayed an unusual double peak in the plasma levels after single doses. Individual subjects had consistent plasma level patterns for each of the four single doses but there was marked intersubject variability in patterns and kinetic parameters. The half-life of unchanged penicillamine ranged from 1.66 to 3.15 hr and the apparent plasma clearance ranged from 530 to 2300 ml/min. The administration of penicillamine following a large breakfast caused a reduction in the area under the penicillamine plasma concentration-time curve corresponding to a decrease in the extent of absorption of unchanged penicillamine.
Adult↗
Free fraction change with differing volume ratios in equilibrium dialysis: cases of non-linear drug-protein binding.
When equilibrium dialysis is used to measure drug-protein binding, an increase in the volume ratio (buffer solution/protein solution) causes a decrease in the total drug concentration at equilibrium. When binding is non-linear, this decrease in total drug-concentration also causes a decrease in the free fraction. By use of the same volume ratio (3:1) binding curves were obtained for the binding of prednisolone to plasma proteins, and for the binding of salicylic acid and tolmetin to human serum albumin (HSA). When the volume ratio was changed, the observed free fractions were appreciably different from those expected by taking into account only the changes in the total equilibrium drug concentration. There is evidence that this phenomenon is the result of competition for binding sites between the drug and an impurity in the HSA. The effects are not the result of the presence of free fatty acids.
Blood Proteins↗
Plasma protein-binding parameters of prednisolone in immune disease patients receiving long-term prednisone therapy.
Prednisone and prednisolone bind in plasma to albumin and transcortin. In am attempt to determine whether prednisone side effects and/or type of disease correlated with prednisolone plasma protein binding, multiple plasma samples from 17 patients (three asthma, eight SLE, three RA, two PSS, one PAN) receiving long-term prednisone therapy were monitored during an interval between two prednisone doses. Prednisolone plasma protein binding was nonlinear and exhibited large intrapatient and interpatient variability. For the group, mean association constants of the prednisolone-albumin complex and the prednisolone-transcortin complex were 2.3 X 10(3) M-1 and 2.9 X 10(7) M-1, with coefficients of variation of 82% and 127%, respectively. SLE patients tended to have lower mean prednisolone association constants for albumin and transcortin than did other patients. The presence of corticosteroid side effects did not correlate with prednisolone plasma protein-binding parameters. The wide range of prednisolone free fraction noted in plasma from patients who achieved comparable total prednisolone plasma concentrations implies that administration of a uniform prednisone dose will not lead to a predictable clinical response.
Adolescent↗
Comparison of methods for estimating digoxin dosing regimens.
Five methods of predicting serum digoxin concentrations (SDCs), used in conjunction with three equations for estimating creatinine clearance, were compared. Radioimmunoassay was used to determine the nadir SDCs in 79 patients (38 men, 41 women) meeting predetermined study criteria. All patients, whose ages ranged from 33 to 94 years, had steady-state digoxin levels, were on oral digoxin, and were free from thyroid dysfunction, malabsorption syndromes, dehydration, and renal failure. Three equations, involving combinations of age, lean body weight, and serum creatinine, were used to estimate creatinine clearance (Clcr). These Clcr values were then used in each of five equations to estimate SDCs. The estimated SDCs were compared to actual SDCs in the 79 patients, and the effects of changing the fraction of dose absorbed and the method of determining Clcr were analyzed. No substantial difference in predictive reliability was evident among the methods studied. Poor correlations existed between observed and calculated SDCs (r less than 0.70), and these correlations were not significantly affected by gender, fraction of dose absorbed, or method of Clcr estimation. Higher correlations were found for the oldest and youngest age groups. Severe limitations are associated with the use of the formulas studied.
Adult↗
Specific and sensitive assays for digoxin in plasma, urine and heart tissue.
A combined internal standard and marker was added directly to urine, then after mixing, an aliquot was injected directly onto a C18 mu-Bondapak HPLC column. The 4.5 ml digoxin fraction was collected over 1.5 min starting 1 min after the appearance of the marker peak (UV detection), and the digoxin determined in the fraction by radioimmunoassay using 3H-digoxin. Digoxin was extracted from alkalinized plasma into dichloromethane. After evaporating the extract and addition of internal standard the remainder of the assay was as described above for urine. Multiple samples of urine and plasma collected in a single dose bioavailability trial in normal human volunteers were assayed by one of these specific methods as well as by the usual direct nonspecific RIA method. There were no significant differences in results by the specific and nonspecific methods. Heart tissue was homogenized with internal standard and phosphate buffer than the mixture was centrifuged. The supernatant was extracted with dichloromethane, the solvent evaporated from the extract, the residue redissolved in mobile phase and the remainder of the assay carried out as for urine and plasma.
Animals↗
Reversible metabolism and pharmacokinetics: application to prednisone-prednisolone.
The simplest three pharmacokinetic models which apply in cases of reversible metabolism are described. Area under the curve (AUC) relationships are described which allow one to make a choice of which one of the three models may apply in a particular case. Expressions for clearances and other pharmacokinetic parameters are given. It is shown that biexponential time courses are expected after bolus intravenous administration although distribution is not involved in the models. In some cases dose/AUC or infusion rate/steady-state concentration yield simple clearances, while in other cases they are complex. AUC data obtained following oral administration of 5 mg doses of prednisone and prednisolone to 16 normal volunteers were analyzed with the new concepts and one of the models was found to apply. This new interpretation of such data results in some significant changes from application of classical pharmacokinetics.
Adolescent↗
The in vitro loss of penicillamine in plasma, albumin solutions, and whole blood: implications for pharmacokinetic studies of penicillamine.
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Albumins↗
Comparative bioavailability evaluation of erythromycin base and its salts and esters. I. Erythromycin estolate capsules versus enteric-coated erythromycin base tablets.
A randomized crossover study in 16 healthy volunteers given multiple doses of erythromycin base enteric-coated tablets or erythromycin estolate capsules revealed essentially no difference in the resultant plasma concentration of bioactive erythromycin. This similarity in bioactivity persisted despite the fact that total eryghromycin levels (bioactive erythromycin base plus bioinactive erythromycin propionate) were at least three times higher after administration of the estolate than after administration of the base.
Adult↗
Oral and intravenous bretylium disposition.
To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.
Administration, Oral↗