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The hypothesis was formerly put forward that the main therapeutic action of cimetidine (the histamine H2-receptor antagonist marketed as Tagamet) as well as some of its side effects might be mediated by its interactions with essential metal ions. The present paper reports the potentiometric study of the coordination of the drug with copper(II) and zinc(II) in NaCl 0.15 mol dm-3 at 37 degrees C. Special attention was paid to copper complexes, due to (i) the involvement of cimetidine in rheumatoid arthritis evolution which could be related to the well-established role of copper against this disease, (ii) the anti-ulcer and anti-inflammatory properties of copper. In particular, the copper-cimetidine-histamine and copper-cimetidine-histidine ternary systems were investigated. Computer simulations of the distribution of cimetidine, zinc and copper in blood plasma were performed at therapeutic levels of the drug. No influence can be expected from cimetidine on the bioavailability of these metal ions, the opposite being also true. The mediation of copper in the action of cimetidine on rheumatoid arthritis should thus be ruled out, the influence of the drug being rather interpretable in terms of reduction of histamine release. Similarly, the sexual dysfunctions due to cimetidine administration are unlikely to arise from the interactions of drug with zinc in blood plasma. The possible involvement of copper and zinc in cimetidine gastrointestinal absorption is also discussed.

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