Tissue pharmacokinetics for prevention of hemodialysis vascular access stenosis.

摘要

The efficacy of local, perivascular delivery of antiproliferative drugs to prevent stenosis depends on the drug distribution at the graft-vessel anastamoses. To determine drug distribution within graft/vessel walls near anastamoses, we performed studies on a porcine arteriovenous graft model following perivascular administration. These results were used to validate a tissue based pharmacokinetic (TBPK) model that was developed to predict the graft/vessel wall concentrations based on in vitro transport parameters.; Expanded polytetrafluroethylene graft was implanted between the carotid artery and jugular vein bilaterally in the pig. During surgery 52 mg of dipyridamole loaded microspheres suspended in ReGelRTM were applied at each anastomosis. At 0.5, 1.5, 4, 8 and 21 days postimplantation, the pigs were euthanized. Sections of graft, adjoining artery and vein were explanted, homogenized and analyzed for drug content. The transport parameters diffusivity and partition coefficient of dipyridamole across vessels and graft walls were obtained using perfusion studies and equilibrium tissue uptake experiments respectively. A TBPK model was developed using these transport parameters and was validated with the in vivo results.; The in vivo results showed that, after the perivascular administration of dipyridamole using a sustained-delivery platform, peak vessel walls concentrations occurred within +/-1 cm of the anastomoses and were sustained for up to 21 days. Transport parameters varied substantially among the vessels. Native femoral veins (3.87 +/- 0.93 x 10-6 cm2/s) were twice as permeable to dipyridamole as were femoral arteries (2.06 +/- 0.79 x 10-6 cm2/s, p 0.01). Explanted grafts (0.64 +/- 0.12 x 10-6 cm 2/s) were the least permeable. Partition coefficients of femoral arteries (4.11 +/- 0.99) were higher than femoral veins (2.05 +/- 0.85, p 0.01) and explanted graft (0.89 +/- 0.56, p 0.01). The TBPK model simulations could successfully predict the extravascular space, graft wall and vessel wall (both arterial and venous) concentrations.; The TBPK model simulations and in vivo studies showed that sustained inhibitory concentrations of dipyridamole, above the IC 50 values from cell culture experiments found to inhibit proliferation of porcine smooth muscle cells, can be achieved by perivascular administration of the drug using our polymeric platforms for approximately 3 weeks.