An estimate of the rate of direct drug diffusion from the surface of heart and kidney--implications for their representation as compartments

In many regional pharmacokinetic experiments and models, the anatomical boundaries of the heart and kidney are intrinsically assumed to be barriers for drug diffusion such that these organs can be represented as one or more compartments. To test this, an experimental preparation was developed in which the heart and kidney of anaesthetized sheep were surrounded with 0.9% saline. The rate of drug diffusion from the surface of the organs into the saline was examined during constant-rate i.v. drug infusions. It was found that the maximum clearances of lidocaine and procainamide into the pericardial saline were 10.3-11.6 and 0.6-2.1 ml min-1 respectively, and the values for the kidney were 0.3-0.6, 0.1-1.0 and 0.4-1.3 ml min-1, for lidocaine, procainamide, and meperidine respectively. These corresponded to calculated times of 4-481 min to reach the steady-state saline concentration depending on the drug and the organ. The steady-state ratio of the saline concentrations over the arterial blood drug concentrations usually ranged from 0.5-1.0. It is concluded that drugs can rapidly enter regions of low or no perfusion surrounding these organs, and that the concept of treating the heart and kidney as compartments may not be valid in certain 'worst-case' situations.