Permeation characteristics of tetracyclines in parallel artificial membrane permeation assay II: Effect of divalent metal ions and mucin

<p class="ADMETabstracttext">The bioavailability of tetracyclines is markedly decreased when co-administered with antacids, milk, or food containing Ca²⁺. Previously, it was suggested that the effective intestinal permeation of tetracycline (TC) was decreased due to Ca²⁺ linked mucin binding in the mucosal side. In the present study, we investigated the effect of Ca²⁺, Mg²⁺, and mucin on the membrane permeation of six tetracyclines (TC, oxytetracycline (OTC), minocycline (MINO), doxycycline (DOXY), demeclocycline (DMCTC), and chlortetracycline (CTC)). The membrane permeability values (P_e) of tetracyclines were measured by the parallel artificial membrane permeation assay (PAMPA) using soybean lecithin – decane (SL–PAMPA) and octanol (OCT–PAMPA) membranes. In SL–PAMPA, Ca²⁺ markedly decreased the P_e values of all tetracyclines. In OCT–PAMPA, Ca²⁺ increased the P_e values of TC, CTC, and DMCTC, but not DOXY, OTC, and MINO. Mg²⁺ decreased the P_e values of all tetracyclines in both SL–PAMPA and OCT–PAMPA (except for CTC in OCT–PAMPA). The addition of mucin had little or no effect in all cases. In contrast to the previously suggested mechanism, the results of the present study suggested that Ca²⁺ chelate formation decreased the membrane permeation of tetracyclines, irrespective of Ca²⁺ linked mucin binding. Molecular speciation analysis suggested that the permeation of TC – metal chelates was negligibly small in SL-PAMPA.</p>