Lack of interaction of digoxin and P-glycoprotein inhibitors, quinidine and verapamil in human placenta in vitro.
OBJECTIVE
To determine the effect of quinidine and verapamil, known antiarrhythmic agents and P-glycoprotein (Pgp) inhibitors, on digoxin transport from the maternal to the fetal compartment in the isolated perfused human placenta.


METHODS
Isolated placental cotyledons from normal human placentae (n=20) were dually perfused with M199 medium enriched with albumin (0.3%) and glucose (0.1%). The maternal and the fetal circulation flow rates were 12 and 6 ml/min, respectively. Closed circulations were used to evaluate steady state transplacental gradient formation. In six placentae quinindine was added to the maternal circuit; after 45 min of perfusion, digoxin was added to the maternal circulation. The effect of verapamil on digoxin transfer from the maternal to the fetal compartments was explored in five placentae. In six additional placentae the transfer of digoxin was studied in the absence of quinidine. Transplacental passage of digoxin was calculated from repeated fetal and maternal perfusate samples. Digoxin levels were determined in perfusate samples by fluorescence polarization immunoassay. Antipyrine was added to the maternal reservoir of all placentae as reference substance.


RESULTS
The transfer of digoxin (alone) and in the presence of quinidine or verapamil was 10.93+/-3.71, 9.00+/-5.2 and 12.94+/-4.86%, respectively. The levels of digoxin in the fetal compartment, 0.62+/-0.20, 0.48+/-0.29 and 0.60+/-0.26 ng/ml, respectively, were not significantly affected by quinidine and verapamil. These Pgp modulators, also did not influence significantly the steady state levels of digoxin in the maternal compartment.


CONCLUSIONS
Neither quinidine nor verapamil affected the transplacental transfer of digoxin in vitro in normal human placentae. In contrast to the other tissues, they do not inhibit Pgp activity in term human placentae.
Holcberg
Gershon
G
Department of Obstetrics and Gynecology, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, PO Box 151, Beer-Sheva 84101, Israel. holcberg@bgumail.bgu.ac.il
Sapir
Olga
O
Tsadkin
Marina
M
Huleihel
Mahmoud
M
Lazer
Simcha
S
Katz
Miriam
M
Mazor
Moshe
M
Ben-Zvi
Zvi
Z
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D009924:Organ Culture Techniques; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011802:Quinidine / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D004077:Digoxin; D014700:Verapamil; D011802:Quinidine