For many orally administered drugs, during their first passage through the GI tract more than half the dose is removed before reaching the systemic circulation (the first pass effect). A drug interaction on such first pass metabolism may greatly alter the anticipated action of that drug. The experimental model uses a small, acute dose of propranolol to a conscious dog. Our preliminary studies show that the bioavailability of propranolol can be increased as much as 400 percent interaction with chlorpromazine, a drug which inhibits the first pass metabolism of propranolol. We wish to investigate the nature of first pass metabolism with primary emphasis on the effects of drug interactions. Studies into the effects of chronic, as well as acute, dosing and dose size on drug metabolism and action are also proposed. All studies will be done in the conscious dog where a model for studying beta blockage is described. The urinary pattern of propranolol metabolism will be quantified with a gas chromatograph/mass spectrometer/computer assay which we have recently developed. Alterations in the physiological action of propranolol resulting from a drug interaction will be compared with changes in its metabolism to identify mechanisms of the interaction. Propranolol concentrations in blood are measured with a fluorometric method. Drugs selected for possible interactions are: isosorbide dinitrate, amitriptyline, hydrochlorothiazide, hydralazine, phenytoin, phenylbutazone and disulfiram. Follwing completion of our propranolol work, we will study another antianginal drug, isosorbide dinitrate (ISDN) in a similar manner. Others have shown that, for ISDN, hypotensive or antianginal actions are only observed when large oral doses are given to overcome the first pass metabolism. For ISDN, we will measure parent and metabolite concentrations by gas chromatography with either electron capture of mass spectrometric detection. Phenobarbital, acetaminophen propranolol, phenylbutazone, disulfiram, chloramphenicol and chlorpromazine have been selected for interaction studies with ISDN.