Comparative study on the inhibition of Na+, K+-activated ATPase activity by chlorpromazine,promazine, imipramine,and their monodesmethyl metabolites

Summary The inhibition of the sodium- and potassium-activated adenosine triphosphatase (Na-K-ATPase, EC 3.6.1.3) activity by chlorpromazine, promazine and imipramine was compared with that by the monodesmethyl metabolites of these drugs. The experiments were performed with a deoxycholate- and sodium iodide-treated microsomal enzyme preparation from rat brain. It was shown in dose-response curves as well as in double-reciprocal Lineweaver-Burk plots of Na-K-ATPase activity against KCl concentration that the monodesmethyl metabolites were stronger inhibitors than their parent compounds. The results obtained with the desmethyl metabolites and imipramine as inhibitors indicate competitive inhibition while the inhibition by chloropromazine and promazine was of mixed type. The experimental data appear to support the following conclusions: 1. General rules of albumin binding of drugs obviously can apply to a drug-enzyme complex. 2. The monodesmethyl metabolites of tricyclic psychoactive drugs may possess a higher affinity to receptors with protein structure.