Accumulation of drugs by guinea pig isolated atria. Quantitative correlations

The time course of the tissue accumulation of 16 neutral, cationic, and anionic drugs by resting and 2-Hz stimulated atria of the guinea pig was measured. The accumulation of the substances was quantified by means of their tissue to medium ratios (T/M). Auricles driven with 2 Hz accumulated the drugs faster and during a long period of time to a greater extent than resting atria. By extrapolation of the binding characteristics, the final equilibrium T/M values were estimated. The variance in these accumulation data at equilibrium (log T/M) Could be best described by a linear combination of log P (octanol/water) and the ability of the drugs to bind to atrial homogenate (log percent bound/percent free). A parameter calculated from protein binding appeared less significant. Comparable results were obtained for the accumulation data measured in resting and 2-Hz stimulated atrial muscles. It is suggested that the degree of accumulation of drugs into atrial tissue is determined by the facility of their penetration of the plasma membrane and the extent of their intracellular binding.