title: Evaluation of the impact of multivalent metal ions on the permeation behavior of Dolutegravir sodium.
abstract: Interactions between active pharmaceutical ingredients (APIs) and polyvalent cations are an important factor within drug absorption in the gastrointestinal tract. Dolutegravir sodium, as a second-generation integrase stand transfer inhibitor for the treatment of HIV was investigated regarding chelation with Al(3+), Ca(2+), Fe(3+), Mg(2+ )and Zn(2+) ions at three different molar ratios. Furthermore, the influence of drug-ion chelates on the permeability of the drug across two intestinal membrane models was analyzed. For this purpose, Caco-2 monolayer model and Ussing chamber technique utilizing freshly excited rat intestinal mucosa were chosen and a buffer system without additional Mg(2+) and Ca(2+) ions was tested regarding cell detachment. The addition of polyvalent cations in an equal molar ratio to the drug solution decreased the dissolved drug by at least 11%. An increased multivalent cation concentration in a ratio of 1:10 afforded an API drop in the solution of at least 88% with the exception of Mg(2+). In particular, Dolutegravir sodium was chelated with iron ions to nearly 100%. Overall, the higher the amount of metal ions in the solution, the lower was the detected amount of the drug. The permeation experiments across the Caco-2 monolayer and the rat intestinal mucosa pointed out that the addition of AlCl3, CaCl2 and ZnCl2 in a molar ratio of 10:1 to the drug led to significantly decreased drug permeation. According to these results the co-administration of Al(3+), Ca(2+ )or Zn(2+ )as well as of supplementary medications containing these polyvalent ions is in case of oral Dolutegravir delivery not recommended.
authors.affiliation: a ThioMatrix GmbH, Research Center Innsbruck , Innsbruck , Austria ;
authors.forename: Julia Anita
authors.initials: JA
authors.lastname: Grießinger
authors.affiliation: b Center for Chemistry and Biomedicine, Center for Molecular Biosciences, Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauptstein
authors.affiliation: b Center for Chemistry and Biomedicine, Center for Molecular Biosciences, Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: b Center for Chemistry and Biomedicine, Center for Molecular Biosciences, Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Kesinee
authors.initials: K
authors.lastname: Netsomboon
authors.affiliation: b Center for Chemistry and Biomedicine, Center for Molecular Biosciences, Department of Pharmaceutical Technology , Institute of Pharmacy, University of Innsbruck , Innsbruck , Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002412:Cations; D002463:Cell Membrane Permeability / Q000187:drug effects*; D056831:Coordination Complexes / Q000032:analysis; D019587:Dietary Supplements; D004347:Drug Interactions; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008670:Metals / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010078:Oxazines; D010539:Permeability; D010879:Piperazines; D011728:Pyridones; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099226:Dolutegravir
chemical_list: D002412:Cations; D056831:Coordination Complexes; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D008670:Metals; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: Cell membrane; Dolutegravir sodium; chelate; multivalent ions; permeation study; rat intestinal mucosa