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Biomedical subjects

J G Wagner

Publications and source records attributed to J G Wagner.

At least 73 records · Page 4Linked to original sources
PubMed1987

Dosage intervals based on mean residence times.

It is shown that a suitable dosage interval, tau, can be estimated by a factor times the sum of the mean residence time (MRT) of the central compartment (MRTC) and the MRT of the absorption site (MRTA). This value of tau will provide a ratio, maximum steady-state plasma concentration: minimum steady-state plasma concentration, which averages approximately 2, such that the percent variation of the steady-state drug concentration is +/- 33%. It is shown that this approach produces vastly improved steady-state concentrations compared with those obtained when the tau value is chosen as equal to the apparent elimination half-life, which, classically, has been the approach usually used. When the drug is administered intravenously, the MRT of the absorption site in the above relationship is equal to zero. Suitable values of the "factor" in the above relationship were found to be 0.75 for the two-compartment open models with bolus iv administration, unity for the one-compartment open model with first-order absorption and elimination, and 1.35 for the classical two-compartment open model with first-order absorption.

Drug Administration Schedule↗
PubMed1986

Lack of first-pass metabolism of ethanol at blood concentrations in the social drinking range.

Previously published data are displayed in a new manner and show that there is complete systemic availability of oral doses of 23-47 g of ethanol (0.35-0.75 g/kg or 30-60 ml of 95% ethanol) in man when administered in the fasting state relative to an intravenous infusion of the same doses administered over a 2-hr period. A previous report by other authors that oral ethanol (0.15 g/kg) in man had a mean systemic availability of only 29% is explained by the fact that the subjects were fed one hour prior to administration of the alcohol and that the intravenous dose was infused over only a 20 minute period.

Absorption↗
PubMed1986

Estimation of theophylline absorption rate by means of the Wagner-Nelson equation.

The elimination rate constant of theophylline to be used in calculating the cumulative amount absorbed per milliliter of the volume of distribution is estimated from terminal theophylline concentrations of the same data set as that analyzed for absorption kinetics. Erroneous results are obtained if the elimination rate constant is obtained from a different treatment such as an oral solution or elixir or from intravenous data, and/or if the wrong asymptotic value is used. So-called "trickle absorption" is shown to be an artifact. Published data indicate appreciable intrasubject variation in the elimination rate constant of theophylline.

Absorption↗
PubMed1986

Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients.

Hepatic arterial catheters were placed for therapy in 8 patients with primary or metastatic liver cancer. Temporary hepatic venous catheters allowed direct sampling of blood for hepatic venous drug concentrations. Patients were administered from three to six infusions at rates of 10, 30, 90, 135, 180, 210, and 270 mg/kg/day (0.053 to 1.43 microM/kg/min), given over 2 h, of 5-fluorouracil (FUra). In Method 1, FUra was infused i.v., and FUra was measured in plasma from hepatic arterial and hepatic venous blood. In Method 2, FUra was given i.v. at one time and infused into hepatic arterial blood at another time, and FUra was measured in plasma from peripheral blood at the same site in both cases. Steady-state FUra plasma concentrations were measured by a sensitive and specific high-performance liquid chromatography method. Data were computer fitted to the equations appropriate for a physiological two-compartment flow model with Michaelis-Menten elimination from the peripheral compartment and blood flow rate, Q, between the central and peripheral compartment. Methods 1 and 2 gave mean Vmax and Km values which did not differ significantly; the overall mean Vmax was 2.02 microM/kg/min, and the overall mean Km was 10.9 microM. For Method 1 the mean Q1 value was 0.0803 liters/(kg X min) or 5.26 liters/min, which is the same as cardiac output, but for Method 2 the mean Q2 value was higher, namely 0.189 liters/(kg X min) or 13.0 liters/min. Steady-state systemic and intrinsic clearances and extraction ratios decreased progressively as the dose rate increased. Intra- and inter-subject variation of both Vmax and Km were of the same order of magnitude. As a result, dose rate escalation should be conservative for dose rates above 135 mg/kg/day. The results support hepatic arterial infusion as a means of improving the therapeutic index of FUra in the treatment of cancer of the liver.

Adult↗
PubMed1985

Effect of protein binding on steady-state equations.

Previously published steady-state equations assumed elimination of total drug. The equations have been derived to cover the case where only free (unbound) drug is eliminated. The equation for oral administration is the same in both cases. The equation for intravenous administration has the same form, but the interpretation of Km is different.

Administration, Oral↗
PubMed1985

A nonlinear physiologic pharmacokinetic model: I. Steady-state.

The two-compartment model of Rowland et al., (2) has been extended by replacing first order elimination with Michaelis-Menten elimination kinetics. All of the equations for steady-state concentrations and clearances for zero order (constant rate) input orally (into compartment #2) and intravenously (into compartment #1) are derived and reported. The steady-state concentration in compartment #1, following intravenous administration, is shown to be a nonlinear function of maximal velocity of metabolism, Vm, the Michaelis constant, Km, and liver blood flow, Q; and, following oral administration is dependent only upon Vm and Km and is independent of Q. However, oral bioavailability is a function of Vm, Km, and Q. The model allows physiologic pharmacokinetic interpretation of both linear and nonlinear data; and, together with simple modification of the model, can explain much observed pharmacokinetic data to date particularly for first-pass drugs. Future articles in the series will be concerned with single doses, evaluation of literature data in terms of the model, application of the theory in toxicology and in clinical pharmacokinetics and therapeutics.

Administration, Oral↗
PubMed1985

Propranolol: pooled Michaelis-Menten parameters and the effect of input rate on bioavailability.

Average steady-state propranolol plasma concentration (Css) were calculated from published steady-state propranolol clearance data for dose rates (Ro) of 40, 80, 160, 240, and 320 mg/ day in divided doses every 6 hours. The Css-Ro data for each of four subjects were fit essentially perfectly by the equation: Css = KmRo/ (Vm-Ro). Very similar Vm and Km values were obtained with the Vmi and Kmi values for four parallel Michaelis-Menten pathways of propranolol metabolism. It is shown by use of the mean Vm and Km values that the propranolol input rate profoundly affects its bioavailability, which is expected for a first-pass drug that follows Michaelis-Menten elimination kinetics after oral dosing. This most likely explains the poor bioavailability of propranolol after a sustained-release formulation. The decreased bioavailability of propranolol when the number of subdivisions of the daily dose is increased is also explained.

Administration, Oral↗
PubMed1985

New and simple method to predict dosage of drugs obeying simple Michaelis-Menten elimination kinetics and to distinguish such kinetics from simple first order and from parallel Michaelis-Menten and first order kinetics.

It has been found empirically that either average or minimum steady-state plasma concentrations (Css) of drugs obeying Michaelis-Menten elimination kinetics give essentially linear plots on semilogarithmic graph paper when Css is plotted versus the maintenance dose (D) or dose rate (R). The equations of such straight lines may be converted to the following nonlinear equation: Css = abD which fits the Css,D data essentially as well as D = VmCss/(Km + Css). The parameter b is analogous to unity plus the interest fraction in logarithmic growth or compound interest calculations, and each drug appears to have a characteristic value of this parameter, with extremely small intersubject variation. From the above equation the following equation, Dn+1 = Dn + 1n(Cn+1/Cn)1n b can be derived, which forms the basis of predicting the needed dosage, Dn+1, to obtain a desired steady-state concentration, Cn+1, using one initial steady-state concentration, Cn, obtained with dose, Dn, and using a population value of b for the drug. It appears that it is the value of the "initial capital" (i.e., a in relation to the initial dose) rather than the "interest fraction" (i.e., b - 1) that causes most of the intersubject variation in Css of a given drug. Several drugs illustrate the usefulness of the method. A semilogarithmic plot also appears to be an excellent method to distinguish simple Michaelis-Menten kinetics from parallel Michaelis-Menten and first order elimination kinetics and from simple first order kinetics with steady-state data in the range 0.3-3 Km.

Anti-Anxiety Agents↗
PubMed1984

Effects of age on the clinical pharmacokinetics of ibuprofen.

The pharmacokinetics of ibuprofen (Motrin) were studied in 17 normal elderly men and women aged 65 to 78 years. Total and free unbound plasma concentrations of ibuprofen were determined 12 hours after single oral doses of 400, 800, and 1,200 mg. These results were then compared with those of a similar study involving 15 normal young men 22 to 35 years old. The two age groups showed no statistically significant differences in any pharmacokinetic parameter studied. Therefore, according to this study, advanced age has only minimal influence on the pharmacokinetics of ibuprofen, and dosage apparently does not need to be adjusted for age.

Adult↗
PubMed1984

Sensitive gas-liquid chromatographic-electron-capture detection method for determination of sobrerol in biological fluids.

A sensitive gas-liquid chromatographic assay for sobrerol in biological fluids has been developed. The assay procedure involves esterification of both hydroxyl groups of sobrerol with pentafluoropropionic anhydride to form the diester which can be quantitated using gas-liquid chromatography-electron-capture detection. The detection limit of plasma sobrerol under the conditions described is 5 ng/ml. The assay procedure permits the measurement of unchanged drug in plasma, whole blood or urine in the presence of its metabolites.

Chromatography, Gas↗
PubMed1984

Pharmacokinetics of ibuprofen in man IV: absorption and disposition.

Fifteen normal male volunteers received 400, 800, and 1200 mg doses of ibuprofen as 1, 2, or 3 tablets, respectively, in crossover fashion, then 420 mg in solution form during the fourth week. Plasma concentration of ibuprofen was measured by an HPLC method. Individual subject concentration-time (C,t) data following the solution were analyzed by two different methods, and results unequivocally indicated the open two compartment model with first order absorption. However, the computer fitting of both arithmetic and geometric mean concentrations led to a different model. A method was developed to obtain absorption data (fraction of drug absorbed, Fa, versus time) for a multicompartmental system from oral data alone, without intravenous data. The method assumes that Vp is constant intrasubject and that absorption is complete following administration of both the solution and tablets. The method was successfully applied to the ibuprofen tablet data. It was shown also that such a method is necessary to obtain ibuprofen absorption data since intrasubject variation of the microscopic rate constants k12, k21, and kel (as reflected by the intrasubject variation of the hybrid rate parameters lambda 1 and lambda 2 or beta and alpha) is of the same order of magnitude as intersubject variation. Absorption of ibuprofen from tablets was shown not to be simple first order as for the solution. The absorption profiles following one tablet were S-shaped, while those following 2 or 3 tablets had partial linear segments indicating zero order absorption.

Absorption↗
PubMed1984

Nonlinear pharmacokinetics of CI-912 in adult epileptic patients.

We studied the pharmacokinetics of CI-912 (1,2-benziosoxazole-3-methanesulfonamide) in 10 adults with refractory partial seizures during an open-label pilot study. Plasma and whole blood concentrations were measured by a high-performance liquid chromatograph method after a single dose and up to and at steady state with one or two dosage regimens. Steady-state clearances averaged only 42% (range 20-60%) of single-dose clearances. Vm and Km values of the Michaelis-Menten equation were calculated for 9 of the 10 patients by a new method: Vm averaged 1,272 (range 500-1,973) mg/day and Km averaged 25.1 (range 9.23-52.5) micrograms/ml. The best initial dosage for a new patient is 300 mg CI-912 every 12 h.

Adult↗
PubMed1983

Pharmacokinetics of ibuprofen in man--III: Plasma protein binding.

Plasma protein binding of ibuprofen was measured by equilibrium dialysis on 406 plasma samples collected from 15 normal volunteers following doses of 400, 800, and 1200 mg of ibuprofen as tablets (N = 102, 100, 104, respectively) and 420 mg as an aqueous solution (N = 100). Individual subject bound concentration at dialysis equilibrium (Cbd) vs. free concentration at dialysis equilibrium (Cfd) were well fitted via computer to the Scatchard equation with one class of binding sites. The binding capacity averaged 1231 microM (range 848-1658 microM), and the association constant averaged 1.76 X 10(5) M-1 (range 1.15 X 10(5) to 2.73 X 10(5) M-1). Distributional analysis was performed on the free fraction (fd) and bound/free ratios (Cbd/Cfd = 1/fd-1) at dialysis equilibrium for each treatment. Using pooled data of all four treatments, distributional analysis was also performed on the free fractions (f) and bound/free ratios (Cb/Cf = 1/f-1) corresponding to the plasma drug concentrations in blood as it was withdrawn from the subjects. The bound/free ratios were normally distributed, whereas the distributions of the free fractions were skewed towards higher values.

Adult↗
PubMed1983

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships.

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.

Administration, Oral↗
PubMed1983

Determination of myocardial and serum digoxin concentrations in children by specific and nonspecific assay methods.

After obtaining samples at open heart surgery, serum and right atrial digoxin concentrations were measured in 25 children by a nonspecific, direct radioimmunoassay method (NS) and by a specific method in which digoxin was separated from its metabolites by HPLC before radioimmunoassay was applied to the digoxin fraction (S). Digoxin was detectable by S assay (sensitivity 0.1 ng/g) in 16 heart specimens and 22 serum samples. The mean and range of the S/NS ratio was 0.74 (0.23 to 2.63) for serum and 0.81 (0.068 to 1.38) for atrial tissue. By NS assay the mean and range of the atrial/serum ratio was 78.1 (2.4 to 340, n = 21) and by S assay the corresponding values were 100 (10.7 to 318, n = 15). A multiple linear regression indicated that 72.5% of the variance of the heart digoxin concentrations measured by S assay were accounted for by the variables height, body weight, daily digoxin dose before operation, plasma digoxin concentration by S assay, and BUN.

Adolescent↗