Vol. 301, Issue 2, 672-678, May 2002

Pharmacokinetic Advantage of Intrapericardially Applied Substances in the Rat

J. J. Rob Hermans, Helma van Essen, Harry A. J. Struijker-Boudier, Randolph M. Johnson, Felix Theeuwes and Jos F. M. Smits

Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Universiteit Maastricht, Maastricht, The Netherlands (J.J.R.H., H.v.E., H.A.J.S.-B., J.F.M.S.); and DURECT Corporation, Cupertino, California (R.M.J., F.T.)

Intrapericardial application of therapeutic agents may open perspectives for target-directed therapy of the diseased heart. This study was performed to investigate whether intrapericardial drug application is beneficial from a pharmacokinetic point of view. Male Wistar rats were provided with intrapericardial and intravascular catheters for substance administration and sampling. Intrapericardial bolus injections of fluorescent macromolecules [fluorescein isothiocyanate (FITC)-rat IgG, molecular weight about 155 kDa; Texas Red rat serum albumin, mol. wt. 67 kDa; Texas Red fibroblast growth factor (FGF), mol. wt. 18 kDa; and FITC heparin, mean mol. wt. 18 kDa] resulted in substance concentrations in pericardial fluid that exceeded those in plasma, for several hours. Pericardial fluid volumes of catheter-instrumented rats, derived from (initial) central compartment volumes, ranged between 0.5 and 0.9 ml/kg. After chronic (7 days) intrapericardial infusions with osmotic minipumps, pericardial fluid/plasma concentration ratios (local advantages) were 7 to 10 for the fluorescent proteins and >30 for FITC-heparin. This can be explained by the low substance clearances in pericardial fluid compared with plasma. Local advantages of the small substances cortisol (mol. wt. = 362.5) and a carbonic acid derivative thereof (mol. wt. = 348) were 14 and 420. Intrapericardial infusion of ¹²⁵I-FGF-2 yielded 8 times higher cardiac tissue levels than systemic infusion, whereas ¹²⁵I-FGF-2 was found in the entire heart. Pharmacokinetic profiles of intrapericardially applied substances are such that desired local drug concentrations can be obtained at lower dosages, whereas systemic concentrations remain low (thus reducing the potential risk of peripheral side effects). Therefore, intrapericardial application of therapeutic agents provides a promising strategy for site-specific treatment of heart or coronary diseases.