Molecular Form of Theophylline Responsible for Positive Inotropic Activity

Abstract

• 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. 1 and Baird and Hardman 2 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 3 have recently demonstrated a linear relationship between the pH of the extracellular perfusion fluid (pH e ) 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. Methods DOG HEART-LUNG PREPARATIONA modification of the Krayer-Mendez 4 denervated henrt-lun<r preparation, as described by Hardman et al., 5 was employed in dogs anesthetized with sodium pentobarbitnl (35 mg./Kg.) to evaluate the cardiac stimulating effects of theophylline and S-chlorotheophylline. The seven dogs which received theophylline had average control readings of: cardiac output, 533 ml./min. (440 to 770); heart rate, 147/min. (120 to Additional studies were performed in which the metabolism of theophylline in the dog heartlung preparation was followed concurrently with its positive inotropic activity. Theophylline blood levels were determined by the silver salt precipitation method of Cornish and Christnmn 0 on protein-free plasma filtrate. The possible presence of 3-methylxanthine was excluded by paper chromatography. The presence of the two remaining known products of theophylline metabolism, 1-methyluric acid and 1,3-dimethyluric acid, was searched for using the method of Buchanan et al. 7 for determining blood uric acid. CAT PAPILLARY MUSCLE PREPARATIONA modification of the procedure described by Cattell and Gold 8 was employed in which an isotonie lever system was utilized mid contraction height was recorded on a smoked paper. The papillary muscles were prepared in the usual manner from a cat anesthetized with ether. The muscles were suspended in 50 ml. of Chenoweth's glucose solution 9 buffered to pH 7.4 and maintained at 37 C. The muscles were stimulated at a frequency of 60 per minute with a square wave pulse for 5 msec, at suprathreshold voltages through adjacent platinum electrodes. A stream of 5 per cent carbon dioxide and 95 per cent oxygen was bubbled vigorously through the solution during the experiment. The muscles were observed for one hour under these conditions and 598

Mode of Action of Chronotropic Agents in Cardiac Purkinje Fibers

“…Theophylline is a methylxanthine and at physiological pH the concentration of the cationic form is negligible (pK = 0.9). Some 5 % is present as anion (see Hardman, 1962). This compound has been widely used in biochemical studies as an inhibitor of phosphodiesterase and it is known to have inotropic effects in heart (e.g.…”

Systemic and regional myocardial responses to AR-L 115 BS, a positive inotropic imidazo-pyridine, in the absence or in the presence of the bradycardiac action of alinidine

“…Its actions on the cardiovascular system show considerable resemblance with xanthines such as theophylline and aminophylline (1,9,13,20,24). Inspection of the ratio between the chronotropic and inotropic effects (maxLVdP/dt) of the most common used sympathomimetic amines indicates that AR-Lll5BS compares favorably with isoproterenol and dopamine, but is second to dobutamine (21,31).…”

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model II: Verification of the Model for Passive Placental Permeability Drugs

“…(Andersin, 1991), whereas zidovudine is a weak acid (Gallicano, 2000). In contrast, theophylline is neutral (Hardman, 1962). a Refers to the SimCYP Simulator compound library (version 14).…”