Metal ion-tetracycline interactions in biological fluids. Part 8. Potentiometric and spectroscopic studies on the formation of Ca(II) and Mg(II) complexes with 4-dedimethylamino-tetracycline and 6-desoxy-6-demethyl-tetracycline.

Effects of metal ion-tetracycline (TC) interactions on both gastrointestinal absorption and pharmacological activity of these drugs are well documented. In particular, recent simulation studies based on newly determined complex stability constants have drawn attention to the potential influence of Ca2+ and Mg2+ ions on the bioavailability of various TC derivatives in blood plasma. Contrary to previous thoughts, it was demonstrated in these studies that the fraction of antibiotic not bound to proteins almost exclusively occurs as calcium and magnesium complexes. Among this fraction, predominant binuclear species are electrically charged, and as such cannot passively diffuse through cell membranes. It was thus postulated that the partial blocking of one of the potential coordination sites of the TC molecule, which would favor the formation of neutral mononuclear complexes, should result in a better tissue penetration of the drug. Such correlations were recently established for specific derivatives. Before possible modifications of the TC molecule can be envisaged, it is necessary that all the chelating sites involved in the relevant complexes be properly assigned. As tetracyclines are very complex ligands, the present paper first deals with the coordination of calcium and magnesium with two simpler parent substances, i.e., 4-dedimethylamino-tetracycline (DTC) and 6-desoxy-6-demethyl-tetracycline (DSC). After the quantitative investigation of the proton and metal complex equilibria involved, UV and circular dichroism spectroscopies are used to study the corresponding structural aspects. In DTC complexes, the BCD ring system acts as the exclusive coordination site for both metals. For DSC, however, the N4 atom plays a leading role in the metal binding and would be the only donor involved in 1:1 species; in ML2 complexes, the second ligand is thought to bind through the BCD ring system.