Molecular Pharmacology, Vol 20, 704-708, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

The Affinity of Various Phenothiazine Drugs for Membranes of Intact Human Erythrocytes and Their Membrane-Transforming Activity

¹ Department of Biochemistry, Kyoto College of Pharmacy, Kyoto 607, Japan

Membrane shape changes of human erythrocytes induced by each of five cationic and two anionic phenothiazines were observed semiquantitatively, and the amounts of the drugs incorporated into erythrocytes or ghosts were determined. Cationic and anionic phenothiazines induced membrane invagination and exvagination on human erythrocytes, respectively. The former drugs were incorporated mainly into the membrane of cells, whereas only a small portion of the latter drugs was incorporated into the membrane and the remainder into the cytosol. The initial concentrations of cationic phenothiazines needed to induce the same extent of shape change decreased in the order promethazine, chlorpromazine, perazine, prochlorperazine, and trifluoperazine, indicating that their shape-transforming activities increase in the same order. The phenothiazines with a halogen atom at position C-2 of the phenothiazine nucleus exhibited higher affinity for the membrane than those with a hydrogen atom. Phenothiazines with the N-methylpiperazinyl group in the side chain showed a stronger effect on membrane shape change than those with the dimethylamino group and with the same nonpolar moiety. The introduction of halogen atom(s) appears to increase the affinity of drugs for the plasma membrane, and the polar head group in the side chain seems mainly responsible for perturbation of the membrane, which leads to induction of a shape change.