Sandra R. Harapat

Role of concentration-dependent plasma protein binding in disopyramide disposition

Plasma disopyramide concentration-time data and plasma protein binding measurements were obtained in 12 patients requiring disopyramide for suppression of their cardiac arrhythmias. The fraction of disopyramide unbound to plasma proteins varies from approximately 0.19 to 0.46 over the therapeutic range of total plasma concentrations (2–8 mg/liter). Data from single and multiple intravenous doses were analyzed using two models based on the hypothesis either that clearance is independent of the total disopyramide plasma concentration (total clearance model) or that clearance is independent of the concentration of disopyramide unbound to plasma proteins (free clearance model). This analysis indicates that only the free clearance model satisfactorily describes the data as a linear system. Using the free clearance model and data obtained from single doses, multiple intravenous infusions were designed for each patient which would rapidly attain and maintain predetermined plasma disopyramide concentrations. The calculated and observed disopyramide concentrations were in close agreement. In the 12 patients studied, at any given total disopyramide plasma concentration, there was an approximately twofold range in the fraction of disopyramide unbound to plasma proteins. Mean plasma protein binding data are therefore of little value in a given patient for predicting free disopyramide concentrations from measurements of total disopyramide concentration. Difficulties in the clinical management of patients receiving disopyramide, resulting from the nonlinear disposition of the usually measured total disopyramide concentrations, are discussed.

Verapamil disposition kinetics in chronic atrial fibrillation

Verapamil disposition was studied in 12 patients with chronic atrial fibrillation. After an intravenous bolus of 15 mg plasma concentration was determined and the data fit to a three‐compartment model. Model independent parameters were calculated and values for half‐life (t½), clearance, and steady‐state distribution volume were 6.3 ± 4 hr, 13.3 ± 7.7 ml/min/kg, and 4.3 ± 1.9 l/kg. The model was used to design a multistep infusion scheme, which was employed successfully to acheive predetermined plasma concentrations. Following single oral doses of 120 mg, plasma levels of verapamil and norverapamil were determined. The elimination t½ for verapamil and norverapamil were 8.2 ±6.1 and 10.5 ± 5.6 hr, respectively. The bioavailability of oral verapamil was 35 ± 16%. During long‐term oral therapy the mean verapamil plasma concentration was twice the value predicted from the single‐dose studies. This suggests that verapamil may have reduced clearance during long‐term oral use.

computer Simulation of the Effects of Alterations in Blood Flows and Body Composition on Thiopental Pharmacokinetics in Humans

Background: Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. Methods: A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. Results: The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half‐life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/‐ 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. Conclusions: The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

Rapid high-pressure liquid chromatographic analysis of verapamil in blood and plasma.

A high-pressure liquid chromatographic assay procedure has been developed for verapamil in blood or plasma. A paired-ion solvent system with a reversed-phase column is employed. The procedure is specific for verapamil and the retention times of the major metabolites are identified. This procedure is sensitive to a lower blood concentration of 1 ng/ml and standard curves were found to be linear up to the highest concentration tested, 500 ng/ml. Several drugs were tested for interference with the assay, but none were found to cause any problems. The procedure is simple, rapid and permits the analysis of up to 25 samples per day.

High-pressure liquid chromatographic analysis of drugs in biological fluids: III. Analysis of disopyramide and its mono-n-dealkylated metabolite in Plasma and urine☆

A high-pressure liquid chromatographic analysis for disopyramide (I) and its mono-N-dealkylated metabolite (II) in plasma and urine is described. The analysis, in which I and II together with an internal standard are chromatographed as ion pairs with heptanesulphonic acid, employs a simple and rapid method of sample preparation. The method is more sensitive, reproducible, and rapid than previously reported gas chromatographic methods.

Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model

Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.

Response optimization of drug dosage: Antiarrhythmie studies with tocainide

The benefits of using antiarrhythmic response to optimize dosage regimens of antiarrhythmic drugs in individual patients have been examined. Graded antiarrhythmic response and simultaneously measured plasma drug concentrations have been obtained in 15 patients receiving multiple oral doses of a new antiarrhythmic, tocainide. Plasma drug concentration‐antiarrhythmic response data from each of 11 subjects responding to the drug have been fitted by a generalized concentration effect function which is valid over the entire range of response. With the use of experimentally determined pharmacokinetic parameters to define the dose‐plasma concentration relations hip and plasma drug concentration‐response parameters estimated for individual patients, simulations were carried out to show the effect of various dosage regimens on antiarrhythmic response in individual patients. Such simulations provide a means of assessing antiarrhythmic effect in the range of clinical interest (80% to 100% of maximum effect), where the antiarrhythmic effect is a non linear function of dose, plasma drug concentration, or their logarithms. The simulations also demonstrate that for identical daily doses and dosing intervals patients show marked variability in antiarrhythmic response.

High-pressure liquid chromatographic analysis of drugs in biological fluids. V. Analysis of acebutolol and its major metabolite.

A high-pressure liquid chromatographic analysis for acebutolol and its major metabolite in blood, plasma and urine is reported. The analysis, in which the above mentioned compounds are chromatographed as ion pairs with dodecyl sulfonic acid, uses a simple and rapid method of sample preparation. The technique is more sensitive and rapid than those previously reported and it has equivalent or better reproducibility. The method is applied to the measurement in blood of acebutolol and its acetyl metabolite after a single oral dose.

Dose-dependent acebutolol disposition after oral administration

The relationship between dose and area under the blood concentration‐time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

High-performance liquid chromatographic method for determining thiopental concentrations in twelve rat tissues: Application to physiologic modeling of disposition of barbiturate

A sensitive, selective and reproducible high-performance liquid chromatographic assay of thiopental concentrations in twelve rat tissues was developed using thiamylal as the internal standard. Samples were homogenized in phosphate buffer, extracted into pentane and chromatographed on a microparticulate octadecyl reversed-phase column using ultraviolet detection at 290 nm. A simple digestive step with collagenase prior to homogenization facilitated analysis of thiobarbiturate in skin. Thiopental extraction recovery from fat exceeded 90%. Assay sensitivity was greater than 1 microgram/ml for tissue and plasma samples as small as 50 microliters. This assay has been applied to physiologic pharmacokinetic studies. The paper also presents typical concentration-time profiles of thiopental in four tissues taken from 74 rats given 20 mg/kg thiopental.