METHADONE - A POTENT INHIBITOR OF RAT-LIVER ALDEHYDE OXIDASE

Several drugs with structural similarities to SKF-525A were tested for their ability to inhibit rat liver aldehyde oxidase using the experim ental antitumour agent N-[(2'-dimethylamino)ethyl]acridine-4-carboxami de (AC; NSC 601316; acridine carboxamide) as substrate. The antihistam ine D-chlorpheniramine, and the antiarrhythmics disopyramide, procaina mide and lignocaine were ineffective in inhibiting this reaction. The antihistamines diphenhydramine, pheniramine, doxylamine, orphenadrine, methapyrilene and pyrilamine, gave IC50, values of 100-500 mu M. The narcotic analgesics D-propoxyphene and, in particular, methadone were potent inhibitors of acridone formation with IC50 values of 15.5 and 0 .31 mu M, respectively. Further analysis indicates mixed non-competiti ve type inhibition by methadone with inhibition constants (K-is and K- ii, respectively) of 0.03 +/- 0.01 (SE) and 0.57 +/- 0.12 mu M.