TY - JOUR
T1 - Rapid stimulating effect of the antiarrhythmic agent amiodarone on absorption of organic anion compounds
AU - Segawa, Masahiro
AU - Ogura, Jiro
AU - Seki, Satoru
AU - Itagaki, Shirou
AU - Takahashi, Natsuko
AU - Kobayashi, Masaki
AU - Hirano, Takeshi
AU - Yamaguchi, Hiroaki
AU - Iseki, Ken
N1 - Funding Information:
Received January 23, 2012; Accepted August 30, 2012 J-STAGE Advance Published Date: September 18, 2012, doi:10.2133/dmpk.DMPK-12-RG-010 *To whom correspondence should be addressed: Ken ISEKI, Ph.D., Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan. Tel. ©81-11-706-3770, Fax: ©81-11-706-3770, E-mail: ken-i@pharm.hokudai.ac.jp †Present address: Department of Pharmacy, Hirosaki University School of Medicine & Hospital, 53, Hon-cho, Hirosaki 036-8563, Japan. ††Present address: Department of Pharmacy, Kobe University Hospital, 2-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. This work was supported in part by a Grant-in-Aid for Young Scientists (A) from Japan Society for the Promotion of Science (JSPS) and a grant from Mochida Memorial Foundation for Medical & Pharmaceutical Research.
PY - 2013
Y1 - 2013
N2 - In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [3H]estrone-3-sulfate (E-3-S) for 5min. The apical-to-basal transport of [3H]E-3-S was significantly increased by AMD. The AMD-stimulated [3H]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (BSP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.
AB - In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [3H]estrone-3-sulfate (E-3-S) for 5min. The apical-to-basal transport of [3H]E-3-S was significantly increased by AMD. The AMD-stimulated [3H]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (BSP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.
KW - Absorption
KW - Amiodarone
KW - Drug-drug interaction
KW - OATP2B1
KW - Organic anion transport
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U2 - 10.2133/dmpk.DMPK-12-RG-010
DO - 10.2133/dmpk.DMPK-12-RG-010
M3 - Article
C2 - 22986710
AN - SCOPUS:84879351516
VL - 28
SP - 178
EP - 186
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
SN - 1347-4367
IS - 3
ER -