Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta.
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.
Rahi
M
M
Department of Pharmacology, Drug development and Therapeutics, University of Turku, Turku, Finland. melissa.rahi@tyks.fi
Heikkinen
T
T
Hakkola
J
J
Hakala
K
K
Wallerman
O
O
Wadelius
M
M
Wadelius
C
C
Laine
K
K
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D000483:Alleles; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001784:Blood Gas Analysis; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D010920:Placenta / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D019258:Saquinavir / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D000255:Adenosine Triphosphate; D019258:Saquinavir