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Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta

Department of Pharmacology, Drug development and Therapeutics, University of Turku, Turku, Finland; Department of Neurosurgery, University of Turku, Turku, Finland

T Heikkinen

Department of Pharmacology, Drug development and Therapeutics, University of Turku, Turku, Finland; Department of Obstetrics and Gynecology, University of Turku, Turku, Finland

J Hakkola

Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland

K Hakala

Department of Pharmacology, Drug development and Therapeutics, University of Turku, Turku, Finland

O Wallerman

Department of Genetics and Pathology, Rudbeck, Uppsala University, Uppsala, Sweden

M Wadelius

Department of Medical Sciences, Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden

C Wadelius

Department of Genetics and Pathology, Rudbeck, Uppsala University, Uppsala, Sweden

K Laine

Department of Pharmacology, Drug development and Therapeutics, University of Turku, Turku, Finland; TYKSLab, Unit of Clinical pharmacology, Turku University Central Hospital, Turku, Finland

Background: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood–tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. Methods: We have studied the dose–response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression (n�=�44) and the transfer (n�=�16) of saquinavir. Results: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. Conclusions: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp–mediated placental transfer of saquinavir.

Key Words: ABCB1 genotype • adenosine triphosphate • P-glycoprotein • placenta • saquinavir

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