Metal ion-tetracycline interactions in biological fluids. Part 7. Quantitative investigation of methacycline complexes with Ca(II), Mg(II), Cu(II) and Zn(II) ions and assessment of their biological significance

Abstract

Previous studies based on computer-simulated distributions of several tetracyclines in blood plasma during treatment have revealed that the fraction of drug not bound to proteins almost exclusively occurs in the form of calcium and magnesium complexes. In contrast to former thoughts, it thus appeared that the bioavailability of tetracyclines should primarily depend on the physicochemical properties of the most predominant of these species rather than on those of the free patent molecules. In particular, the possible formation of electrically charged homo- or heterobinuclear complexes with the above two metals at the expense of their neutral diffusible mononuclear homologues should notably reduce the bioavailability of the drug. The substitution of electron-attracting groups at positions 5–7, which tends to weaken the electron density of the phenolic diketone moiety, should help to prevent the formation of such binuclear complexes. This hypothesis recently proved valid for chlortetracycline but not for demethylchlortetracycline. Before future developments involving other possible structural changes can be envisaged, the present paper reports an investigation of the coordination of methacycline with Ca(II), Mg(II), Zn(II) and Cu(II) ions, the influence of the methylene group at C6 being expected to resemble that of the chlorine at position 7. Corresponding results show that the methylene substituent does effectively prevent methacycline from generating binuclear complexes with calcium and magnesium, and its effect on copper and zinc coordination is similar. Potential biological implications are discussed on the basis of pertinent computer simulations.