An assessment of the physiological significance of cimetidine interactions with copper and zinc in biofluids as based on the computer-simulated distribution of the involved complexes at therapeutic levels of the drug

Abstract

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.

Metal ion-tetracycline interactions in biological fluids. Part 5. Formation of zinc complexes with tetracycline and some of its derivatives and assessment of their biological significance

“…The standard stock solution of zinc chloride in diluted hydrochloric acid was prepared from crystals supplied by Merck as a 'pro analysi' product, and was titrated for its metal and mineral acid contents as described earlier [11].…”

“…The titration unit was similar to that previously described [11,17,18]. The evolution of the e.m.f, of an electrochemical cell of the type G.E./Antibiotic, Zn 2 § NaC1 (0.15 mol.dm-3)/NaCt (satd) /Hg2Clz-Hg (1) was monitored by a digital mV-meter Beckman Model 4500.…”

“…The extremely low level of the reactant concentrations as well as the lability of the generated complexes actually preclude any conventional experimental investigation. Fortunately, the latest advances in the application of computing science to such biochemical problems has made it possible to design large computer models capable of simulating the percentage distribution of several thousands of complexes in various biofluids [11][12][13][14][15][16].…”

“…In recent years, there has been a growing concern about the possible interference of pharmaceuticals with the bioavailability and metabolism of essential trace metal ions [1][2][3][4][5][6][7][8][9][10][11]. Indeed, organic substances used for therapeutic purposes very often contain donor groups likely to form stable complexes with metal ions occurring naturally in biological fluids.…”

Potentiometric and spectrophotometric studies of MnII and NiII cimetidine complexes

“…From computer simulations, it was possible to verify that cimetidine did not influence zinc or copper bio-availability in the blood plasma at therapeutic levels of the drug. 12 Another study, performed for a series of effective H 2 antagonists of histamine has shown that all ligands containing a guanidinethiazole fragment coordinate Cu II ions through two nitrogen donors. The adjacent thioether sulfur may also be involved in metal-ion binding, contributing to the stabilities of the complexes formed.…”