O-28 Placental transfer of the immunosuppressive drug tacrolimus and its effects on placental function; relevance for renal transplant recipients?

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BackgroundThe number of pregnancies in the kid-ney transplant patient population is high. During gesta-tion these women continue using immunosuppressant drugs, but knowledge about their placental disposition and toxicity is scarce. We now investigated placental transfer of the immunosuppressive drug tacrolimus (TAC) as well as the potential effects on trophoblast cell viability and barrier function.MethodsIsolated dual side perfusions of human pla-cental cotyledons were performed to study disposition of TAC. Additionally, clinical data on TAC concentrations in placental tissue of kidney transplant recipients and ma-ternal whole blood concentrations were gathered. BeWo choriocarcinoma cells were used to evaluate effects on trophoblast cell viability, while interaction with placental ATP-binding cassette transporters was studied in mem-brane vesicles derived from HEK293 cells recombinantly overexpressing human Breast Cancer Resistance Protein (BCRP) or P-glycoprotein (P-gp).ResultsWe found that maternal perfusate levels de-creased during 180 min of perfusion, while being unde-tectable in the fetal circulation. At t=180 min a concen-tration of 220±50 nM was measured in placental tissue, which is almost 100-fold higher than the maternal per-fusate concentration. Analysis of placental tissue of renal transplant recipients revealed a 13-fold higher tacrolimus concentration compared to the maternal blood concen-tration (88±7 nM and 6.8±1.1 nM, respectively). TAC did not affect BeWo cell viability up to the maximum concen-tration of 1 µM tested. In transporter studies we did find stimulation of P-gp-mediated transport and inhibition of BCRP-mediated transport, at 1 and 10 µM, respectively.ConclusionTAC demonstrates strong accumulation in placental tissue and distribution across the tissue was not homongenously. However, the tissue concentrations reached are unlikely to affect trophoblast cell viability or BCRP and P-gp transport function.

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