Metal ion-tetracycline interactions in biological fluids. Part 3. Formation of mixed-metal ternary complexes of tetracycline, oxytetracycline, doxycycline and minocycline with calcium and magnesium, and their involvement in the bioavailability of these antibiotics in blood plasma

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Abstract
The equilibria of the complexes formed separately by calcium and magnesium with tetracycline, oxytetracycline, doxycycline and minocycline were studied in the previous parts of this series. Computer simulations run on this occasion showed that the stoichiometry of these species do actually condition the bioavailability of the antibiotics in blood plasma during treatment, the fraction of free base being quite negligible with regard to the metal-bound one. The present paper completes this study with the investigation of the mixed-metal complexes given rise to by calcium and magnesium with the same antibiotics. Such ternary species have been proved to exist for tetracycline, oxytetracycline, and minocycline. Their involvement in the plasma distribution of these drugs is discussed, in relation with the potential abilities of the four tetracyclines to diffuse from plasma into tissue membranes.