Molecular form of theophylline responsible for positive inotropic activity.

• The purpose of this paper is to identify the active molecular species of a drug, theophylline, which exists simultaneously in the ionized and nonionized states at pH 7.4. Previous studies by Hardman et al. and Baird and Hardman have related changes in cardiac function to the concentration of nonionized or ionized drugs in the extracellular fluid perfusing isolated hearts. Such correlations do not establish the active form of the drug but do provide some insight into the probable active form. Waddell and Hardman have recently demonstrated a linear relationship between the pH of the extracellular perfusion fluid (pHe) and the pH of intracellular water (pH|) in turtle ventricular tissue when pH(. is varied over a range of 6.5 to 9.5. This information may be utilized to identify the active molecular species of ionizable drugs since intracellular, as well as extracellular, concentrations of the ionized and nonionized drug forms in their respective aqueous phases can be estimated simultaneously and correlated with the pharmacological activity of the drug under investigation.