Journal of Pharmacokinetics and Biopharmaceutics

The pharmacokinetics of furosemide in normal man reported from a number of investigators show great discrepancies. We have evaluated the effect on derived pharmacokinetic parameters of furosemide of using different weighting factors or fewer data points to fit the same set of data to an exponential equation, or using noncompartmental analysis. Terminal half-lives of furosemide differed vastly, as did the volume of distribution, but to a lesser extent. The plasma clearance was rather consistent with the different methods used. Thus the discrepancies of the pharmacokinetics of furosemide may, in large part, be due to different methods of analysis of the data. The terminal half-life was most subject to errors of method and the plasma clearance the least.

Gentisamide (2,5-dihydroxybenzamide, GAM), a substrate that forms two monosulfates at the 2 and 5 positions (GAM-2S and GAM-5S) and a monoglucuronide at the 5 position (GAM-5G), was delivered at 8 or 80 μM by normal (N) and retrograde (R) flows to the once-through rat liver preparation. At the lower (8 μM) input concentration, ratios of conjugate formation rate, GAM-5S/GAM-5G and GAM-2S/GAM-5G, were decreased significantly (4.01±1.42 to 2.93±0.99, and 1.13±0.65 to 0.66±0.41, respectively) whereas a small but significant increase in the steady-state extraction ratio, E (0.89±0.029 to 0.94±0.016), was observed upon changing the flow direction from N to R. At the higher input GAM concentration (80 μM), conjugate formation rate ratios were relatively constant for GAM-5S/GAM-5G (1.18±0.08 to 1.11±0.12) and GAM-2S/GAM-5G (0.33±0.05 to 0.31±0.05) upon changing flow direction from N to R, despite a slight increase in E from 0.87±0.023 to 0.91±0.016 was observed. These results suggest that the sulfotransferase activities responsible for 2- and 5-sulfoconjugations are identically distributed and localized anterior to 5-glucuronidation activities during a normal flow of substrate into the rat liver (entering the portal vein and exiting the hepatic vein), and that the presence of uneven distribution of conjugation activities is discriminated only at the lower input drug concentration. At high concentration (>Km for all systems), saturation of all pathways occurs, and other, anteriorly/identically distributed competing pathways would fail to perturb downstream intrahepatic drug concentrations arid the resultant conjugation rates. The lack of change in metabolic profiles renders the condition unsuitable for examination of uneven distribution of enzymes in the liver. These observations were generally predicted by theoretical enzymic models of consistent distribution patterns. Because 2- and 5-sulfation were mediated by systems of similar Km but different Vmax values, two possibilities, the same isozyme of sulfotransferase being involved in the formation of two enzyme-substrate complexes to form two distinctly different products or two isozymes of sulfotransferases of identical distribution, were discussed.

This note gives expressions for recirculation mean time parameters of the disposition kinetics of particles in a semihomogeneous stationary linear system. In such a system each compartment may have an arbitrary single-pass disposition function, rather than a known parametric (usually monoexponential) one. Such systems provide a generalization of physiological flow models. Given observations of arterial blood concentrations and tissue amounts, and making the additional assumptions that (i) the fraction of total blood flow exiting each tissue that goes to each other tissue is constant and known, and (ii) the fraction of drug entering each tissue that is eliminated to the outside is constant and known, the input to each tissue can be known, and therefore both its total blood flow and its single-pass disposition function can be estimated. Recirculation mean time parameters can be computed from these estimates. Application to real thiopental data is presented as an example.

Disposition pharmacokinetics of bismuth following oral dosing of ranitidine bismuth citrate are complicated and variable. An analysis of data from healthy volunteers suggests a model with three disposition compartments and first-order absorption. Patient data are pooled from 10 separate studies and consist of 1140 trough concentrations measured in 802 patients following dosing of 2 to 12 weeks duration. There are therefore insufficient data to obtain reliable parameter estimates for the full model and we use instead a much reduced model and an informative prior based on the volunteer data. Individual parameter estimates from this model can then be used to establish covariate relationships. Trough concentrations were influenced by the coadministration of clarithromycin and by creatinine clearance. A simulation study was carried out to check the validity of the estimates obtained from the reduced model. We carry out analysis via Bayesian sampling-based techniques. Throughout, we use predictive distributions for both diagnostic and inference purposes. In particular, we determine predicted distributions for the Cmax , Cmin and AUC characteristics of new individuals.

Two examples are given to show how Metzler's nonlinear regression program can be used to estimate parameters in a model with multiple dosing. The model of one example is a set of equations involving sums of exponentials, whereas the other model is a set of differential equations reflecting first order absorption and Michaelis-Menten excretion. In both cases no data were given in one of the dosing intervals.

The following conclusions may be drawn from this study's results:

Computer simulations were performed using a one-compartment open model with either first-order or zero-order input and either Michaelis-Menten or Michaelis-Menten and first-order elimination. Twelve theoretical cases constructed from various combinations of typical and atypical values for phenytoin pharmacokinetic parameters, V max and K m , were examined. In many cases, at least 90% of the eventual steady-state serum level would be achieved within 4 weeks when phenytoin was administered at an appropriate rate. In the case of a low-to-average Vmax value and an average-to-high Km value, an initial maintenance dose of 3–4 mg phenytoin sodium/kg/day would, within a few days, result in serum phenytoin levels above the usual therapeutic range. On the other hand, if V max and K m values were both low (3.8 mg/kg/day and 1.45 mg/liter, respectively), a very slow rate of accumulation would ensue. Thirty days after the start of 4 mg phenytoin sodium/kg/day, a serum level of about 16 μg/ml would likely occur. The magnitude of continued accumulation beyond this level would be significantly influenced by the rate of renal elimination of unchanged phenytoin. It is recommended that, after initiation or adjustment of phenytoin therapy, serum phenytoin levels be monitored weekly for 3–4 weeks, then monthly for 2 additional months. Long-term follow-up should include serum phenytoin levels every 3– 6 months or as clinically indicated. Appreciation of the characteristics of phenytoin accumulation in relation to rate of administration and individual pharmacokinetic parameters is important for accurate interpretation of serum phenytoin levels and rational adjustment of dosage regimens.

Different mixed-effects models were compared to evaluate the population dose–response and relative potency of two albuterol inhalers. Bronchodilator response was measured after ascending doses of each inhaler in 37 asthmatic patients. A linear mixed-effects model was developed based on the approach proposed by Finney for the evaluation of bioassay data. A nonlinear mixed-effects (Emax ) model with interindividual and interoccasion variability (IOV) in the different pharmacodynamic parameters was also fit to the data. Both methods produced a similar estimate of relative potency. However, the estimate of relative potency was 22% lower with the nonlinear mixed-effects model if IOV was not taken into account. Monte Carlo simulations based on a similar study design demonstrated that more biased and variable estimates of ED50 and relative potency were obtained when the nonlinear mixed-effects model ignored the presence of IOV in the data. Furthermore, the linear mixed-effects model that did not account for IOV produced confidence intervals for relative potency that were too narrow and thus could lead to erroneous conclusions. These problems were avoided when the estimation model could account for IOV. Results of the simulations were consistent with those of the experimental data. Although the linear or the nonlinear mixed-effects model may be used to evaluate population dose–response and relative potency, there are important differences in the assumptions made by each method.

The pH of water affects the accumulation of weak electrolytes by fish in the water. However, the relationships among water pH, weak electrolyte pKa and the rate and extent of accumulation of the weak electrolyte are poorly characterized. To better define these relationships, goldfish were immersed for varying periods of time in solutions of sulfonamides that were buffered at pHvalues from 5.4 to 9.4. Sulfapyridine, sulfisomidine, and sulfadimethoxine were chosen for investigation, because their pKa's, 8.4, 7.4, and 5.9, respectively, bracketed the pH of fish body fluids. Each fish carcass was assayed for the amount of sulfonamide that had accumulated. Several pharmacokinetic models were used to analyze the data. The model that best described the accumulation of the sulfonamides represented the fish as a single compartment having an apparent volume of distribution (V)and clearance constants for absorption of both the nonionized (kHA and ionized (kA)forms. Values of Vwere between 5 and 60% of the body weight of the fish. Values for kA were all approximately 0.2 μl/min/g fish, while values of kHA were 3–100 times larger than the corresponding kA values. The kHA values correlated with the isoamyl acetate/ water partition coefficients of the nonionized forms. The extent of accumulation of the sulfonamides showed two pH-independent regions, with the low pHregion having the greater accumulation. The pHmidway between the two regions was equal to the pKa of the sulfonamide. The accumulation half-lives were 1.5–4.5 hr and independent of the pHof the water.