An in vitro investigation of the relationships between potency, lipophilicity, cytotoxicity and chemical class of representative calcium antagonist drugs.

Interrelationships that might exist between potency, lipophilicity and cytotoxicity of the chemically diverse calcium antagonist group of drugs have been examined in the present study. The potency of 11 representative calcium antagonists in inhibiting KCl-induced contractions in rabbit isolated aortic rings and their relative lipophilicity was determined using reversed phase HPLC. Their cytotoxicity in rat hepatocyte primary cultures was also determined. Cytotoxicity failed to correlate with potency, except for the highly lipophilic, non-selective, diphenylalkylamines (DPAs), suggesting that cytotoxicity was not caused by blockade of plasmalemmal voltage-operated calcium channels. Cytotoxicity moderately correlated with relative lipophilicity, the most lipophilic drugs also being the most cytotoxic. Relative lipophilicity may partly determine the cytotoxicity and pharmacological potency of Ca++ antagonists in a broad sense, but this correlation was not valid in each individual chemical series. We suggest that the higher cytotoxicity of the DPAs is at least partly due to a greater incorporation of the drugs into the hepatocyte plasmalemma compared to compounds in other chemical classes investigated. Further studies are required to elucidate the particular cytotoxic mechanisms involved.