The interaction of carbamazepine and promethazine in rabbits has been investigated. The influence of this interaction on the processes of biotransformation in the liver was revealed. The drugs were administered as single oral doses (100 mg of each drug) as well as simultaneously with an interval of 15 min. The sequence of administration of the drugs was varied. The influence of promethazine on the pharmacokinetics of carbamazepine is expressed by: (a) strong suppression of carbamazepine's level in plasma and appearance of multiple peaks of carbamazepine; (b) suppression of biotransformation of carbamazepine into carbamazepine-10,11-epoxide at the initial stages and its increase in the intermediate stages. These data are explained by the active capture of carbamazepine by liver at its primary transferal through the liver and sufficient presystem elimination of carbamazepine in the presence of promethazine. The character of kinetic curves of promethazine varies substantially under the influence of carbamazepine. However, this change is not as strong as in case of carbamazepine. The concentration of promethazine in plasma varies slightly and multiple peaks are not observed. The rate of terminal elimination of promethazine varies and abrupt prolonged segments of elimination appear at the initial and terminal stages of the process in return. These data perhaps indicate the induction of biotransformation of promethazine in the presence of carbamazepine-an inductor of microsomal liver enzymes. The changes of kinetics of promethazine and carbamazepine by simultaneous administration as compared with their administration separately, as well as a comparative consideration of pharmacokinetics of promethazine and carbamazepine by simultaneous administration show the existence of competition in the elimination between these drugs and the periodic saturation of liver for their biotransformation.

A highly‐sensitive microcolumn HPLC method for the simultaneous determination of carbamazepine and carbamazepine‐10,11‐epoxide in human serum and saliva is described. The method was successfully employed for the study of pharmacokinetics of carbamazepine in humans. After oral administration of 100 and 200 mg of carbamazepine to a volunteer, multiple peaks were observed on the kinetic curves. They were symbathic in the serum and saliva. This indicated the presence of multiple peaks which characterize both free and protein‐bound fractions of the drug. The existence of multiple peaks on the kinetic curves implies that the kinetic of carbamazepine cannot be described with the one‐compartment linear model. Nevertheless, each peak was treated within the range of a one‐compartment linear model of absorption and the results obtained were compared with published data. For the elucidation of the nature of multiple peaks the graphical differentiation of ascending and descending branches of all peaks were carried out. On this basis the dependence of the absorption and elimination rates on time was constrained. The analysis of experimental data resulted in the following conclusions: (a) the presence of multiple peaks on the kinetic curves is induced by the interrupted character of carbamazepine absorption that is caused by the very poor solubility of carbamazepine; (b) the elimination of the drug from blood serum occurs in two phases. Binding of carbamazepine with tissues takes place in the first phase, and biotransformation and excretion occurs in the second phase. It is possible that the presence of multiple peaks on the kinetic curves is partially caused also by redistribution of the drug from the comparatively easily accessible to the less accessible tissues. This requires further investigation. © 1997 by John Wiley & Sons, Ltd.

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The interaction of carbamazepine and chlorpromazine in rabbits has been studied. The drugs were administrated as single oral doses (200 mg of each drug). The sequence of administration of the drugs was varied. It has been established that by simultaneous administration these drugs decrease absorption of each other in plasma. This may be explained by competition of the drugs to transfer from the gastrointestinal tract into plasma, as well as by the formation of complexes, more or less stable and more or less bound to gastrointestinal tissues. Carbamazepine intensifies the biotransformation of chlorpromazine, which may be caused by the ability of carbamazepine to induce microsomal liver enzymes. Chlorpromazine suppresses the biotransformation of carbamazepine, however. This may be caused by intensive capture of chlorpromazine by liver tissues and by its intensive biotransformation, which in turn is conditioned by its surface-active nature and by the increase of its metabolism with carbamazepine. Therefore the biotransformation of chlorpromazine is increased and metabolism of carbamazepine is reduced. The sequence of administration of the drugs affects their pharmacokinetics significantly.

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