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

Sachika Yamauchi,Kiyohiko Sugano,Daisuke Inoue

doi:10.5599/admet.797

Abstract

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 (Pe) 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 Pe values of all tetracyclines. In OCT–PAMPA, Ca2+ increased the Pe values of TC, CTC, and DMCTC, but not DOXY, OTC, and MINO. Mg2+ decreased the Pe 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.

Highlights

Co-administration of multivalent metal ions reduces the bioavailability of various drugs, such as tetracyclines, fluoroquinolones, HIV-integrase inhibitors, and platelet-stimulating agents [1,2,3,4]
We reported that the Pe value of TC was markedly affected by the composition of phospholipids in parallel artificial membrane permeation assay (PAMPA) [30]
We previously reported that the Pe value of TC in soybean lecithin (SL)-PAMPA was not affected by the ionic strength up to 2 mol/L [34]

Summary

Introduction

Co-administration of multivalent metal ions reduces the bioavailability of various drugs, such as tetracyclines, fluoroquinolones, HIV-integrase inhibitors, and platelet-stimulating agents [1,2,3,4]. The bioavailability of tetracyclines is markedly decreased when co-administered with antacids, milk, and food containing Ca2+ [4,5,6,7,8,9,10]. It is generally accepted that chelate formation between tetracycline (TC) and Ca2+ is behind the observed decrease in the bioavailability of tetracyclines [11,12,13,14,15,16]. Chelate formation of tetracyclines has been extensively investigated The exact mechanism of the Ca2+ effect on the bioavailability of tetracyclines has not been clear.

Objectives

Results

Conclusion