INFLUENCE OF PH ON THE UPTAKE AND PHARMACODYNAMICS OF QUINIDINE IN THE ISOLATED-PERFUSED RAT-HEART

Using the single-pass isolated perfused rat heart preparation we examined the effect of perfusate pH (pH 7.05, 7.46, 7.71, 7.92) on quinidine output concentration (C(out)) and DELTAQT. Eight hearts were perfused at 2.5 mL/min. with quinidine (20 muM) for 35 min. followed by a 35-40 min. washout period with drug-free perfusate. This procedure was repeated four times in each preparation with the pH sequence varied and the same pH used in the first and last phases. Increasing pH slowed the rate of equilibration of C(out), the equilibration rate constant (k) decreasing from 0.273 min.-1 at pH 7.05 to 0.095 min.-1 at pH 7.92. A modified Kety-Renkin-Crone equation was fitted to the C(out) versus time data for each pH. The estimated volume of distribution (V) increased significantly with pH from 11.5 +/- 1.1 to 32.5 +/- 2.9 ml/g, but the permeability surface product did not change with pH (mean 17.7 ml/min./g). There was a linear relationship between V and calculated un-ionised quinidine C(out), with an intercept of 5.70 ml/g corresponding to the V of ionised drug. This indicates that ionised and un-ionised drug readily enter the heart and that the slower equilibration with pH is due to the increased V which results from increased partitioning of un-ionised quinidine into myocardial tissue. Perfusion pH did not directly affect baseline QT interval, but the rate of attainment of maximum DELTAQT decreased with increasing perfusate pH. Plots of DELTAQT versus calculated coronary output quinidine concentration did not change with pH, showing that this drug effect was due to both ionised and un-ionised moieties. This study shows that myocardial permeability and pharmacodynamic effect (DELTAQT) of quinidine are not influenced by perfusion pH over the range 7.0 to 7.9, although rate of equilibration of both C(out) and effect vary with pH.