Volume 2, Number 3/4, p. 85-88
Marina Rukhadze1,Maka Alexishvilii1, Maya Gonashvili1, Nino Sidamonidze2.
Influence of dose on the pharmacokinetics of promethazine in rabbits. Comparison of pharmacokinetics of promethazine and chlorpromazine
The influence of dose on the pharmacokinetics of promethazine was investigated via administration of 100, 200 and 400 mg of the drug to 3 kg rabbits as a single oral dose. The time dependence of the concentration of promethazine in the plasma, as well as the variation of the rates of absorption and elimination during the course of the overall process, were studied. At the low dose (100 mg), the kinetic curve of promethazine is somewhat sigmoid and the rate of absorption increases during the process. At the higher doses of promethazine (200 and 400 mg) multiple peaks are observed in the kinetic curves, the rates of absorption are abruptly increased in comparison with the 100 mg dose and the characters of variation of absorption rate during the process differ not only from the 100 mg case, but also from each other. For the interpretation of these data the following notions were developed: (1) successive exploitation of new sections of the intestine during transit of the drug through it; (2) different permeabilities of the various parts of the intestine; and (3) the possible presence of so-called “absorption windows”. The elimination of promethazine during the final stages of the process proceeds according to a zeroth order law. The fast redistribution of drug through the organs and tissues is presumably determined by the surface active nature of promethazine. Finally, the pharmacoki-netics of promethazine and chlorpromazine were compared. The considerable difference in the pharmacokinetics of these compounds, despite their similar structures (both are derivatives of phenothiazine), is conditioned by both the different intensity of the hepatic first-pass effect and different binding with the tissues of the intestine. The differences may in turn be due to the different surface activities of promethazine and chlorpromazine.
Keywords: absorption windows, chlorpromazine, pharmacokinetics, promethazine, surface activity.