Pharmacokinetics and consistency of pericardial delivery directed to coronary arteries: Direct comparison with endoluminal delivery

Background and hypothesis: Pharmacologic modulation of the contents of the pericardial space has been shown to influence the response of coronary arte ries to balloon injury. Endoluminal (EL) local delivery of various drugs in to coronaries has been found to be limited by short residence time, as well as by highly variable deposited agent concentration. We hypothesized that compounds placed into the pericardial space (P) would penetrate into corona ry tissue with greater consistency than seen after EL delivery and provide for prolonged coronary exposure to agents. Methods and Results: I-125-labeled basic fibroblast growth factor (bFGF), p latelet-derived growth factor (PDGF), albumin, or I-131-labeled diazeniumdi olated albumin (NONO-albumin) were delivered as model/therapeutic proteins into the porcine pericardial space (n = 15 pigs) or into coronaries using a n EL delivery catheter (n = 48 arteries). In subjects receiving I-125-label ed proteins, the delivery target or mid-regions of the left anterior descen ding (LAD) and left circumflex (LCx) arteries were harvested at 1 h or 24 h for gamma-counting and autoradiography, and fractional intramural delivery (FID) or retention measured as percent agent in 100 mg artery/agent in inf usate for both time points. In the animals receiving I-131-labeled NONO-alb umin, serial gamma imaging was employed to evaluate the rate of redistribut ion in individual animals following either pericardial or endoluminal deliv ery. At 1 h, FID values ranged from 0.00064 to 0.0052% for P delivery (medi an 0.0022%), and from 0.00021 to 6.7 for EL delivery (median 0.27%). At 23 h, FID values ranged from 0.00011 to 0.003 for P delivery (median 0.0013), and from 0.0002 to 1,4 for EL delivery. The estimated T1/2 for bFGF redistr ibution from the vascular tissue was 22 h (P) and 7 h (EL), respectively, w hile the directly determined T1/2 values fur NONO-albumin redistribution fr om the delivery region were 22.2 h (P) and 2.5 h (EL). Conclusions: These data show that pericardial fluid contents can access cor onary arteries with intramural concentrations which typically vary by 10-15 -fold, while EL delivery results in a remarkably wide intramural concentrat ion range with up to 33,000-fold variability The apparent redistribution ra te is more rapid following EL delivery, possibly clue to sustained diffusiv e tissue loading from the pericardial space. Pericardial delivery appears t o offer substantial advantages over EL administration with respect to resid ence lime and reproducibility.