Role of P-glycoprotein in the pharmacotherapy of pregnant women

This review addresses the function of the protein-transporter glycoprotein-P (Pgp, ABCB1 protein) and the expression of its encoding gene MDR1/mdr1 throughout the gestational period in humans and animals. We discuss the relationship between the transporter function and the hormone fluctuations during pregnancy. We cite studies on the association between the MDR1/mdr1 gene polymorphisms and the hemato-placental barrier permeability for Pgp substrates, as well as fetal malformations. Under a separate section, drugs commonly used in pregnant women are characterized in terms of their roles as substrates, inducers or inhibitors of the Pgp transporter.

Assessment of drugs belonging to inhibitors and inductors of p-glycoprotein in vitro

The article describes modern approaches for testing of drugs belonging to substrates and inhibitors of P-glycoprotein (Pgp, ABCB1-protein, MDR1-protein) according to the recommendations of Food and Drug Administration (United States) and European Medicines Agency. In vitro methods on cell lines with hyperexpression of the transporter are presented. The same analysis was done on human colon adenocarcinoma cell line (Caco-2).

P-glycoprotein functional activity in «soviet chinchilla» rabbits during pregnancy

P-glycoprotein (Pgp, ABCB1-protein) is a membrane transporter protein that plays the key role in pharmacokinetics of drugs with a broad spectrum of action. Substrates of this transporter are some medical drugs (antibacterial, antiretroviral, hypotensive) that are prescribed to pregnant women for long-term intake, sometimes throughout the whole gestation period. Aim to study the activity of Pgp on the organism level in rabbits of Soviet Chinchilla breed in pregnancy. Materials and Methods. The study was performed on 21 Soviet Chinchilla female rabbits (3000-3500 g). The animals were divided into 3 series. The first series (n=6) included rabbits with 7 days of pregnancy; the second series (n=5) - animals with 14 days of pregnancy; the third series (n=10) - rabbits with 21 days of pregnancy. 7 Days before the study and in the indicated gestation periods, functional activity of Pgp was assessed by the pharmacokinetics of marker transporter substrate – fexofenadine, after its single oral introduction (67.5 mg/kg). Besides, serum concentrations of progesterone, estradiol, testosterone and prolactin were determined by radio immune method Results. In all the studied gestational periods, serum concentrations of estradiol, testosterone and prolactin did not significantly differ from those before pregnancy, but the level of progesterone in blood serum was significantly elevated above the norm. On the 7th day of pregnancy pharmacokinetic parameters of fexofenadine did not show any reliable changes as compared to the initial va-lues. On the 14th day of pregnancy a reliable increase in Cmax, AUC0-t, T1/2 of fexofenadine was noted as compared to the parameters before pregnancy, which indicates a decrease in Pgp functional activity on the organism level. On the 21st day of pregnancy Cmax of fexofenadine remained elevated. Other pharmacokinetic parameters of fexofenadine did not show reliable changes. Conclusion. Reduction in Pgp functional activity, determined by the pharmacokinetics of its marker substrate (fexofenadine), was noted in rabbits of Soviet Chinchilla breed on the 14th and 21st days of pregnancy with the underlying significant increase in progesterone level.

ANALYSIS OF ATTRIBUTION OF NOOPEPT TO SUBSTRATES AND MODULATORS OF FUNCTIONAL ACTIVITY OF ABCB1-PROTEIN IN IN VIVO EXPERIMENT

In the article the influence of nootropic drug Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) on the functional activity of ABCB1-protein is analyzed and attribution of this drug to the transport protein substrates is studied on male Chinchilla rabbits. Functioning of the transport protein was estimated by the pharmacokinetics of its marker substrate - fexofenadine. Fexofenadine was introduced intragastrically one time in the dose 67,5 mg/kg b.w. before and after 14-day introduction of Noopept in the dose 10 mg/kg b.w. 3 times a day. The quantity of the substance was determined by HPLC method according to the previously developed procedure.Belonging of Noopept to ABCB1-protein substrates was estimated by comparison of its pharmacokinetic parameters before and after a course of introduction of verapamil (the known inhibitor of the ABCB1-protein) into male rabbits in the dose 20 mg/kg b.w. 3 times a day. The pharmacokinetics of Noopept was studied by the original HPLC method.It was found that the course of Noopept introduction did not lead to any reliable changes in the pharmacokinetic parameters of the ABCB1-protein marker substrate - fexofenadine, which may evidence preservation of the functional activity of the given transport protein at the initial level. It was also found that the pharmacokinetics of Noopept remained unchanged after a course of introduction of ABCB1-protein inhibitor - verapamil - in to the male rabbits, that is, Noopept is not a substrate of the given transport protein.

The effectiveness and safety of pharmacotherapy against the background of application of Gliquidone

The study was carried out to investigate using rabbits in vivo effect of Gliquidone on functional activity of protein-carrier of glycoprotein-P (P-gp, ABCB1-protein). The activity of P-gp was evaluated according pharmacokinetics of its marker substrate - Fexofenadine after single endogastric introduction. The application of Gliquidone in dosage of 10 mg per 1 kg of body mass during 14 days resulted in no alteration of concentration of Fexofenadine, period of its partial ejection, area under pharmacokinetic curve “concentration-time” from zero to last point of blood sampling, area under pharmacokinetic curve “concentration-time” from zero to infinity and also time of holding of marker substrate, total clearance and absorption coefficient. All this testifies absence of effect of Gliquidone on functional activity of protein-carrier at the level of integral organism. No alterations of pharmacokinetic parameters of Fexofenadine at the 5th day of cessation of Gliquidone were observed.