Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation

Yuki Enoki, Norihiro Suzuki, Motoyasu Ito, Eri Uchiyama, Nagomi Kishi, Chihiro Ito, Yuki Kitahiro, Kazuki Sakamoto, Kazuaki Taguchi, Yuta Yokoyama, Junko Kizu, Kazuaki Matsumoto

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Raltegravir (RAL) that can form chelates with multivalent metal cations shows lateral interactions with multivalent metal cation and polycationic polymer. We investigated the interactions of RAL with multivalent metal cation preparations, Al(OH)3 and LaCO3, and polycationic polymer preparations, bixalomer (Bxl) and sevelamer (Svl). Methods: Immediately before the oral administration of 40 mg/kg RAL, the rats were administered orally with the vehicle, Al(OH)3, LaCO3, Bxl, or Svl, and the time course of RAL serum concentration was followed. The in vitro binding affinity of RAL with multivalent metal cation and polycationic polymer was also evaluated using isothermal titration calorimetry (ITC). Results: When Al(OH)3, LaCO3, Bxl, or Svl was concomitantly administered with RAL, the maximum concentration and area under the curve were significantly lower than those when RAL was administered alone. ITC showed the interaction of RAL with Al(OH)3 as an enthalpy-driven reaction and its interactions with LaCO3 and Bxl as entropy–enthalpy mixed reactions. Conclusions: The interaction of RAL with Al(OH)3, LaCO3, Bxl, or Svl can inhibit RAL absorption into the gastrointestinal tract, and thus, the multivalent metal cation and polycationic polymer are the modifying factors that can affect RAL pharmacokinetics.

Original languageEnglish
Pages (from-to)1361-1369
Number of pages9
JournalJournal of Pharmacy and Pharmacology
Volume72
Issue number10
DOIs
Publication statusPublished - 2020 Oct 1

Keywords

  • bixalomer
  • chelate
  • lanthanum carbonate
  • raltegravir
  • sevelamer

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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