研究等業績 - 原著論文 - 赤嶺　由美子

Effect of coadministration of single and multiple doses of rifampicin on the pharmacokinetics of fexofenadine enantiomers in healthy subjects

Kusuhara H.

Drug Metabolism and Disposition ( Drug Metabolism and Disposition )  41 ( 1 ) 206 - 213   2013年01月

研究論文（学術雑誌）  

The effect of rifampicin on the pharmacokinetics of fexofenadine enantiomers was examined in healthy subjects who received fexofenadine alone or with single or multiple doses of rifampicin (600 mg). A single coadministered dose of rifampicin significantly decreased the oral clearance (CL tot/F) and renal clearance (CLr) of S- and R-fexofenadine by 76 and 62%, and 73 and 62%, respectively. Even after multiple doses, rifampicin significantly decreased these parameters, although the effect on the CLtot/F was slightly blunted. Multiple doses of rifampicin abolished the difference in the CLtot/F of fexofenadine enantiomers, whereas the stereoselectivity in the CLr persisted. Rifampicin inhibited the uptake of fexofenadine enantiomers by human hepatocytes via organic anion transporter (OAT) OATP1B3 and its basal-to-apical transport in Caco-2 cells, but not OAT3-mediated or multidrug and toxic compound extrusion 1 (MATE1) - mediated transport. The plasma-unbound fraction of S-fexofenadine was 1.8 times higher than that of R-fexofenadine. The rifampicin-sensitive uptake by hepatocytes was 1.6 times higher for R-fexofenadine, whereas the transport activities by OATP1B3, OAT3, MATE1, or P-glycoprotein were identical for both enantiomers. S-fexofenadine is a more potent human histamine H1 receptor antagonist than R-fexofenadine. In conclusion, rifampicin has multiple interaction sites with fexofenadine, all of which contribute to increasing the area under the curve of fexofenadine when they are given simultaneously, to surpass the effect of the induction of P-glycoprotein elicited by multiple doses. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

DOI PubMed

Psychotropic Drug–Drug Interactions Involving P-Glycoprotein

Yumiko Akamine, Norio Yasui-Furukori, Ichiro Ieiri, Tsukasa Uno

CNS Drugs ( Springer Science and Business Media LLC )  26 ( 11 ) 959 - 973   2012年11月

研究論文（学術雑誌）  

DOI

Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes

Hideo Shiohira, Norio Yasui-Furukori, Satoshi Yamada, Tomonori Tateishi, Yumiko Akamine, Tsukasa Uno

Pharmaceutical Research ( Springer Science and Business Media LLC )  29 ( 8 ) 2310 - 2316   2012年08月

研究論文（学術雑誌）  

DOI

Different Effects of the Selective Serotonin Reuptake Inhibitors Fluvoxamine, Paroxetine, and Sertraline on the Pharmacokinetics of Fexofenadine in Healthy Volunteers

Junji Saruwatari, Norio Yasui-Furukori, Takenori Niioka, Yumiko Akamine, Ayaka Takashima, Sunao Kaneko, Tsukasa Uno

Journal of Clinical Psychopharmacology ( Ovid Technologies (Wolters Kluwer Health) )  32 ( 2 ) 195 - 199   2012年04月

研究論文（学術雑誌）  

DOI

Carbamazepine differentially affects the pharmacokinetics of fexofenadine enantiomers

Akamine Y.

British Journal of Clinical Pharmacology ( British Journal of Clinical Pharmacology )  73 ( 3 ) 478 - 481   2012年03月

研究論文（学術雑誌）  

Aim: This aim of this study was to characterize the impact of the P-glycoprotein (P-gp) inducer, carbamazepine, on fexofenadine enantiomer pharmacokinetics. Methods: Twelve healthy volunteers initially received a 60mg dose of fexofenadine alone. Subsequently, a 100mg dose of carbamazepine was administered three times daily (300mg day -1), and on day 7, fexofenadine was co-administered. Results: Carbamazepine significantly decreased the area under the plasma concentration-time curve and the amount excreted into the urine of (S)- and (R)-fexofenadine. The P-gp inducer showed a greater effect on the pharmacokinetic parameters of (S)-fexofenadine. Conclusion: This study indicates that carbamazepine may alter the pharmacokinetics of fexofenadine enantiomers. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

DOI PubMed

The Role of Drug Transporters on Psychotropic Penetration of the Blood–Brain Barrier

Akamine Yumiko, China Kayoko, Uno Tsukasa

Clinical Neuropsychopharmacology and Therapeutics ( 日本臨床精神神経薬理学会 )  3   8 - 14   2012年  [査読有り]

研究論文（学術雑誌）  

At the Blood–Brain barrier (BBB), the superfamily of ATP-binding cassette (ABC) transporters includes the ABCB1 subfamily corresponding to P-glycoprotein (P-gp), the ABCC subfamilies of multidrug resistance-associated proteins (MRPs), and the ABCG2 subfamily corresponding to breast cancer resistance protein (BCRP). These efflux transporters are located mainly in the endothelial cells forming the BBB and prevent the entry of xenobiotics into the brain. Since psychotropics act on target sites of the central nervous system (CNS) in the brain, it is very important to know these transporters' roles at the BBB and to determine the brain drug concentrations at the targeted sites of the CNS. However, there is little information on human brain concentrations of psychotropics. Recent studies have demonstrated that brain concentrations of many psychotropics are significantly higher in P-gp-knockout mice than in wild-type mice. This result implies that P-gp may be a key player in the regulation of brain psychotropic pharmacokinetics and possibly causes the P-gp-mediated drug interaction at the BBB. In this review, we discuss the current findings concerning the role of drug transporters on the concentrations of psychotropics in the brain and summarize the available in vivo studies related to psychotropics.

DOI CiNii Research

遺伝子情報を臨床で有効に生かすには テーラーメイド治療に向けて

赤嶺 由美子, 宇野 司

九州薬学会会報 ( 九州山口薬学会 )  ( 65 ) 7 - 12   2011年10月

研究論文（学術雑誌）  

薬剤師にとってゲノム薬理学情報が医薬品適正使用推進のための重要なツールとなることは明らかである。薬物代謝酵素ならびに薬物トランスポーターの遺伝子多型とその臨床的意義について概説すると共に、薬剤師にとって臨床上重要な遺伝子変異(バイオマーカー)について述べた。代表的な薬物代謝酵素としてCYP2C19、CYP2D6、CYP2C9、CYP3A5、薬物トランスポーターとしてP-gp、OATPs、注目すべき遺伝子変異としてKRAS遺伝子、EGFR遺伝子を挙げた。

A sensitive column-switching HPLC method for aripiprazole and dehydroaripiprazole and its application to human pharmacokinetic studies

Yumiko Akamine, Norio Yasui-Furukori, Midori Kojima, Yoshimasa Inoue, Tsukasa Uno

Journal of Separation Science ( Wiley )  33 ( 21 ) 3292 - 3298   2010年11月

研究論文（学術雑誌）  

DOI

Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers

Akamine Y.

Xenobiotica ( Xenobiotica )  40 ( 11 ) 782 - 789   2010年11月

研究論文（学術雑誌）  

This study investigated an association of SLCO (encoding organic anion-transporting polypeptides (OATP), 1B1, 1B3, and 2B1), ABCB1 (P-glycoprotein (P-gp)), ABCC2 multidrug resistance protein 2 (MRP2), and ABCG2 (breast cancer resistance protein (BCRP)) polymorphisms with fexofenadine enantiomer pharmacokinetics after an oral dose of fexofenadine (60mg) in 24 healthy subjects. The area under the plasma concentration-time curve (AUC 0-24) of S-fexofenadine, but not R-fexofenadine, was significantly lower in subjects with a SLCO2B1*1/*1 allele as compared to subjects with a *3 allele (p0.031). The AUC024 of S-fexofenadine was significantly lower in subjects with a wild-type combination of SLCO2B1*1/*1/ ABCB1 1236CC, SLCO2B1*1/*1/ABCB1 3435CC, SLCO2B1*1/*1/ ABCC2-24CC, and ABCB1 1236CC/3435CC/ABCC2-24CC compared to other polymorphic genotypes (p0.010, 0.033, 0.022, and 0.036, respectively), whereas there was no difference in the AUC024 between the SLCO1B1/1B3 plus ABCB1 and ABCC2 groups. The pharmacokinetic properties of S-fexofenadine are affected by a single polymorphism of SLCO2B1 in combination with several polymorphisms of ABCB1 C1236T, C3435T, and ABCC2 C-24T. However, the ABCG2 polymorphism was not associated with fexofenadine pharmacokinetics. These findings suggest that a combination of multiple transporters, including OATP, P-gp, and MRP2, reacts strongly to fexofenadine exposure in the small intestine and liver, resulting in different dispositions of both enantiomers. © 2010 Informa UK, Ltd.

DOI PubMed

P糖たんぱく質を介した薬物相互作用の臨床研究 Fexofenadine各光学異性体の体内動態

赤嶺 由美子, 宇野 司

医薬品相互作用研究 ( (一社)医薬品相互作用研究会 )  33 ( 2 ) 45 - 50   2010年01月

研究論文（学術雑誌）  

フェキソフェナジンはヒスタミンH1受容体拮抗薬であり、アレルギー性疾患の治療薬として広く使用されている。フェキソフェナジンはR体とS体の光学異性体を持つラセミ化合物で、両方の光学異性体は臨床的に等しい薬理作用をもつが、体内動態は異なる挙動を示す。光学異性体間における薬物動態の違いについて概説した。また、P糖蛋白質阻害剤であるイトラコナゾールとベラパミル、P糖蛋白質誘導剤であるカルバマゼピンと、フェキソフェナジン光学異性体との薬物相互作用について述べた。

Effects of the P-glycoprotein Inducer Carbamazepine on Fexofenadine Pharmacokinetics

Satoshi Yamada, Norio Yasui-Furukori, Yumiko Akamine, Sunao Kaneko, Tsukasa Uno

Therapeutic Drug Monitoring ( Ovid Technologies (Wolters Kluwer Health) )  31 ( 6 ) 764 - 768   2009年12月

研究論文（学術雑誌）  

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