TY - JOUR
T1 - Concurrent administration with multivalent metal cation preparations or polycationic polymer preparations inhibits the absorption of raltegravir via its chelation
AU - Enoki, Yuki
AU - Suzuki, Norihiro
AU - Ito, Motoyasu
AU - Uchiyama, Eri
AU - Kishi, Nagomi
AU - Ito, Chihiro
AU - Kitahiro, Yuki
AU - Sakamoto, Kazuki
AU - Taguchi, Kazuaki
AU - Yokoyama, Yuta
AU - Kizu, Junko
AU - Matsumoto, Kazuaki
N1 - Funding Information:
This work was supported by the Japanese Society for the Promotion of Science [KAKENHI KK-15K-0810].
Funding Information:
This work was supported by the Japanese Society for the Promotion of Science [KAKENHI KK‐15K‐0810].
Publisher Copyright:
© 2020 Royal Pharmaceutical Society
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - bixalomer
KW - chelate
KW - lanthanum carbonate
KW - raltegravir
KW - sevelamer
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U2 - 10.1111/jphp.13330
DO - 10.1111/jphp.13330
M3 - Article
C2 - 32657432
AN - SCOPUS:85087791800
SN - 0022-3573
VL - 72
SP - 1361
EP - 1369
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
IS - 10
ER -