A potentiometric method for the in vitro adsorption kinetic study of an ionic micromolecule to charcoal, based on the continuous direct monitoring of the micromolecule free concentration by means of an ion-selective electrode (ISE), has been developed. A chlorpromazine ISE was constructed and used to study the adsorption kinetics of the drug on pure activated charcoal and two commercial formulations (Ultracarbon tablets and Carbomix powder). The method consists of the rapid addition of a slurry containing the charcoal into the drug solution under stirring at pH 1.2 (to simulate a gastric fluid environment) and continuous recording of the electrode potential until the establishment of equilibrium The drug free concentration at appropriate time intervals was calculated from the recorded adsorption curve acid the apparent adsorption rate constant was estimated assuming first order kinetics. Within run RSD of the estimates ranged from 0.3 to 12% (mainly less than 5%), while between run RSD (n=3) ranged from 1 to 19% (mainly less than 10%). A linear relationship was found between the apparent adsorption rate constants and the amount of charcoal used with slopes following the rank order activated charcoal>Ultracarbon tablets>Carbomix powder. These results were explained on the basis of different surface areas of the adsorbents. The work proved the usefulness of ion-selective potentiometry in adsorption studies and can be extended to other ionic drugs for which selective electrodes can be constructed.

Purpose. To point out the importance of heterogeneity in drug distribution processes and develop a noncompartmental approach for the description of the distribution of drug in the body. Methods. A dichotomous branching network of vessels for the arterial tree connected to a similar venous network was used to describe the heterogeneity of blood flow in the successive generations of the networks. The relevant kinetics of drug distribution in the well perfused and the deep tissues was considered to take place under well stirred (homogeneous) and understirred (heterogeneous) conditions, respectively. Results. A `'homogeneous model'' with classical kinetics (which is mathematically equivalent with the one-compartment model) was developed for these drugs which are confined to well perfused (''well stirred'') spaces. A `'heterogeneous model'' was proposed for the drugs reaching understirred spaces using a decreasing with time rate coefficient (fractal kinetics) to model the diffusion of drug under heterogeneous conditions. The analysis of the model equations revealed that the homogeneous model can be considered as a special case of the heterogeneous model. Concentration-time plots of multiexponential type were generated using the heterogeneous model equation. The empirically used power functions of time for the analysis of calcium clearance curves, were found to be similar to the equation adhering to the heterogeneous model. Fittings comparable to multiexponential models were obtained when the heterogeneous model equation with only one adjustable parameter was applied to six sets of long period calcium data. Conclusions. The heterogeneous processes of drug distribution in the body can obey the principles of fractal kinetics. Calcium clearance curves were analysed with the heterogeneous model. The validity of multicompartmental models which are based on the concept of homogeneity to describe drug distribution should be reconsidered.

Background: This investigation war undertaken to study: a) the adsorption characteristics of chlorpromazine to activated charcoal and its formulations Carbomix(R) powder and Ultracarbon(R) tablets at gastric pH; b) the effect on chlorpromazine adsorption of polyethylene glycol and its combination with electrolyte lavage solution; c) the effect of the order of addition of polyethylene glycol-electrolyte lavage solution. Method: Ion selective electrode potentiometry, bared on the selective, direct and continuous response of a chlorpromazine-ion selective electrode to the concentration of the free drug, was used. Successive additions of microvolumes of a chlorpromazine solution were made into a charcoal slurry in acidic medium of pH 1.2 with measurement of the chlorpromazine-ion selective electrode potential at equilibrium Results: The maximum adsorption capacity values of activated charcoal, Carbomix and Ultracarbon, were 297, 563, and 382 mg/g respectively, while the affinity constant values were 40.2, 70.4, and 40.5 L/g, respectively. The adsorption of chlorpromazine to each of the Ultracarbon and Carbomix components was compared to the total adsorption of the formulations. The addition of polyethylene glycol-electrolyte lavage solution causes a slight desorption of chlorpromazine from activated charcoal at gastric pH, more pronounced when polyethylene glycol-electrolyte lavage solution follows the addition of activated charcoal, suggesting the possibility of a nonspecific binding of chlorpromazine to polyethylene glycol. The amount of chlorpromazine adsorbed to Carbomix and Ultracarbon was not significantly affected at gastric pH by the presence of polyethylene glycol or polyethylene glycol-electrolyte lavage solution added either concurrently or sequentially to these formulations.