Over the past decade there has been a tremendous increase in the use of the calcium channel blockers in the treatment of a variety of cardiovascular diseases. The three major agents of this class of drugs are verapamil, nifedipine and diltiazem. The disposition and metabolism of these drugs is not fully clear. This is especially true in situations which they are commonly used, i.e. during long term treatment and in the presence of other drugs. A major objective of the studies in this proposal will be to evaluate in the dog animal model the effects of route of administration and drug interactions have on the steady-state kinetics, metabolism and pharmacodynamics of each one of these calcium channel blockers. The interacting drugs that will be used will be the beta receptor blocker propranolol, and the H2 - receptor blocker cimetidine. In addition, the effects of steady-state dosing of each of the calcium channel blockers have on the pharmacokinetics, pharmacodynamics and metabolism of propranolol will also be investigated. The plasma levels of diltiazem and its active metabolites, deacetyl-and demethyldiltiazem, will be measured by UV-HPLC. Nifedipine plasma levels will be measured by electron capture-gas chromatography. The optical isomers of propranolol, its active metabolite 4-hydroxypropranolol, verapamil and its active metabolite norverapamil, will be measured by GC-MS techniques using stable isotopes of the parent isomers. Urinary metabolism studies will employ radio isotopic, HPLC, HPLC-MS, and GC-MS analytical techniques. The pharmacological action of propranolol and each of the calcium channel blockers will be assessed over the time course of the specific experiments. Proporanolol and its active metabolites beta receptor blocking activity will be quantitated as a function of their ability to inhibit isoproterenol induced tachycardia. The pharmacological action of verapamil and diltiazem and their active metabolites will be measured as a function of their negative dromotropic action on A- V conduction; while nifedipine's action will be measured as a function to lower blood pressure and modeled using effect models. Pharmacokinetic, metabolic and pharmacodynamic data will be generated simultaneously. Such type of analysis will be extremely valuable for the clinician, by providing information on the dose effect relationship of the calcium channel blockers and propranolol. This information will also be valuable to the pharmacologist by providing insight into possible mechanisms responsible for alterations due to differences in the route of administration and to drug interactions.
