研究等業績 - 原著論文 - 赤嶺 由美子
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Influence of everolimus on the pharmacokinetics of tacrolimus in Japanese renal transplant patients
Niioka T.
International Journal of Urology ( International Journal of Urology ) 23 ( 6 ) 484 - 490 2016年06月
研究論文（学術雑誌）
Objectives: To examine whether a trough concentration of everolimus in the therapeutic range of 3-5 ng/mL affects the pharmacokinetics of tacrolimus in renal transplant patients. Methods: A total of 52 Japanese renal transplant patients receiving tacrolimus were enrolled in this study. In 28 of them, everolimus was co-administered on day 14 after surgery. Changes in the dose-adjusted blood trough concentration of tacrolimus from day 14 to 28 after surgery were investigated. Results: The dose-adjusted blood trough concentration of tacrolimus on day 28 was affected by CYP3A5*3/*3 and hemoglobin level (P < 0.001 and P = 0.007), but not by everolimus (P = 0.171). In addition, there was no change in the dose-adjusted blood trough concentration of tacrolimus in patients before or after everolimus coadministration (P = 0.165). On day 28, there was no correlation between the rate of change in the dose-adjusted blood trough concentration of tacrolimus and the blood trough concentration or area under the plasma concentration-time curve from 0 to 12 h for everolimus after initiation of combination therapy (r = 0.341, P = 0.076 and r = 0.234, P = 0.231). Conclusions: A pharmacokinetic interaction between tacrolimus and everolimus was not observed clinically in renal transplant patients. Safe and reliable immunosuppressive therapy in renal transplant patients might be achieved using a combination of tacrolimus and everolimus.
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Akamine Y.
Drug Metabolism and Pharmacokinetics ( Drug Metabolism and Pharmacokinetics ) 30 ( 5 ) 352 - 357 2015年10月
研究論文（学術雑誌）
The stereoselective pharmacokinetics of fexofenadine are associated with OATP2B1-mediated transport, and grapefruit juice (GFJ) is an inhibitor of OATP2B1. Therefore, in this study, we aimed to investigate whether and to what extent GFJ ingestion affected the pharmacokinetics of fexofenadine enantiomers in healthy subjects. In a randomized, two-phase, open-label, crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or GFJ. Ingestion of GFJ significantly decreased the areas under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 39% and 52%, respectively. Subsequently, GFJ increased the mean R/S ratio of the AUC0-24 from 1.58 to 1.96 (P < 0.05). Although GFJ greatly reduced the amounts of (R)- and (S)-fexofenadine excreted into the urine (Ae0-24) by 52% and 61%, respectively, the mean R/S ratios of Ae0-24 and the renal clearances of both enantiomers were unchanged between the control and GFJ phases. GFJ, an OATP2B1 inhibitor, significantly reduced the plasma concentrations of fexofenadine enantiomers, exhibiting clinically moderate effects. The present results suggested that changes in OATP2B1 activity by GFJ may alter the stereoselective pharmacokinetics of fexofenadine and that reduced intestinal OATP2B1 activity may affect the stereoselectivity of fexofenadine.
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Multiple inductive effects of carbamazepine on combined therapy with paliperidone and amlodipine
Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 40 ( 4 ) 480 - 482 2015年08月
研究論文（学術雑誌）
Summary What is known and objective Carbamazepine is a potent inducer of cytochrome P450 3A and P-glycoprotein. However, there are no reports of the effects of carbamazepine on more than one co-administered drug. Case summary A 53-year-old female patient with schizophrenia and hypertension was on paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine was added to this prescription, the plasma concentrations of both drugs decreased dramatically in a dose-dependent manner. Although the patient's psychotic symptoms did not change, as a result, her mean blood pressure increased to 160·1/103·6 mmHg from 138·4/91·4 mmHg at a carbamazepine dose of 600 mg/day. What is new and conclusion Theses cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together. Carbamazepine is a potent inducer of CYP3A and P-glycoprotein. This cases show the effect of carbamazepine induction on two drugs simultaneously. Care is required when carbamazepine is added to drug regimens including paliperidone or amlodipine alone or together.
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Determinants of the Stereoselective Pharmacokinetics of Fexofenadine
Yumiko Akamine
YAKUGAKU ZASSHI ( Pharmaceutical Society of Japan ) 135 ( 3 ) 473 - 481 2015年03月
研究論文（学術雑誌）
Drug transporters play an important role in the clinical pharmacokinetics of many therapeutic agents. Although it is estimated that about half of all therapeutic agents are chiral, there has been little information on the stereoselective pharmacokinetics related to drug transporters. This review focuses on the drug transporters contributing to the stereoselective pharmacokinetics of fexofenadine enantiomers in humans. Fexofenadine is administered clinically as a racemic mixture, and the plasma concentration of (<i>R</i>)-fexofenadine is about 1.5-fold higher than that of the (<i>S</i>)-enantiomer. Because fexofenadine is poorly metabolized by cytochrome P450s, its pharmacokinetics depends on its drug-transporter activities. First, we examined whether drug-transporter polymorphisms influence fexofenadine enantiomer pharmacokinetics. The findings suggested that a combination of multiple transporters involving organic anion transporting polypeptide (OATP) 2B1, P-glycoprotein (P-gp), and multidrug resistance-associated protein 2 (MRP2) react to stereoselective fexofenadine exposure. Subsequently, we evaluated the roles of P-gp and OATPs in fexofenadine enantiomer pharmacokinetics using these inducer/inhibitors. Coadministration of P-gp inducer/inhibitors significantly altered the pharmacokinetics of fexofenadine enantiomers. In addition, the OATP inhibitors rifampicin and apple juice also affected fexofenadine enantiomer pharmacokinetics. Moreover, in <i>in vitro</i> studies, the uptake of both fexofenadine enantiomers into OATP2B1 cRNA-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (<i>R</i>)-fexofenadine. Taken together, these studies indicated that multiple transporters including P-gp, OATPs, and MRP2 play important roles in fexofenadine enantiomer pharmacokinetics. Furthermore, OATP2B1 is a key determinant of the stereoselective pharmacokinetics of fexofenadine, and drug transporters may have chiral discrimination ability.<br>
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 40 ( 1 ) 98 - 103 2015年02月
研究論文（学術雑誌）
What is known and objective Rifampicin is a potent inducer of P-glycoprotein (P-gp) and inhibitor of organic anion-transporting polypeptides (OATPs), with fexofenadine acting as a substrate for both mechanisms. Simultaneous administration of single- or multiple-dose rifampicin 600 mg significantly increases the concentrations of fexofenadine enantiomers by inhibiting OATP transporters. However, the effects of rifampicin 450 mg are unknown. Here, we evaluated the effects of multiple doses of rifampicin 450 mg on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese volunteers. Methods In this randomized, two-phase, double-blind crossover study, 10 healthy volunteers received rifampicin 450 mg/day or placebo for 7 days. On day 7, fexofenadine 60 mg was co-administered simultaneously. Results and discussion Rifampicin significantly increased the mean area under the plasma concentration-time curve (AUC) of (R)- and (S)-fexofenadine (3·10-fold and 3·48-fold, respectively) and decreased the renal clearance of (R)- and (S)-fexofenadine (0·40-fold and 0·47-fold, respectively), causing marked differences in the mean amounts of these enantiomers excreted into the urine in the rifampicin phase (P < 0·001). These results indicated that multiple doses of rifampicin 450 mg may be sufficient to inhibit the renal influx transporter and OATP-mediated hepatic uptake of both enantiomers. Moreover, these effects may be greater than the P-gp-inductive effects of rifampicin. Therefore, the interactive mechanism of multidose rifampicin may occur through a combination of OATP and P-gp transporters, thereby altering the pharmacokinetics of fexofenadine enantiomers. What is new and conclusions In this study of rifampicin 450 mg, the interactive magnitude of the mean AUC values of fexofenadine enantiomers was higher than that observed in the previous study of rifampicin 600 mg, and no dose-dependent inhibitory effects of rifampicin were observed. These effects may be clinically significant in patients receiving fexofenadine and rifampicin. The AUC of (R)- and (S)-fexofenadine by 450 mg of rifampicin, is a potent inducer of P-glycoprotein and inhibitor of OATPs, rather than 600 mg increased. Interactive mechanism of rifampicin multiple doses seems to occur through a combination of OATP and P-glycoprotein.
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Effects of one-time apple juice ingestion on the pharmacokinetics of fexofenadine enantiomers
Akamine Y.
European Journal of Clinical Pharmacology ( European Journal of Clinical Pharmacology ) 70 ( 9 ) 1087 - 1095 2014年09月
研究論文（学術雑誌）
Purpose: We examined the effect of a single apple juice intake on the pharmacokinetics of fexofenadine enantiomers in healthy Japanese subjects. Methods: In a randomized two phase, open-label crossover study, 14 subjects received 60 mg of racemic fexofenadine simultaneously with water or apple juice. For the uptake studies, oocytes expressing organic anion-transporting polypeptide 2B1 (OATP2B1) were incubated with 100 μM (R)- and (S)-fexofenadine in the presence or absence of 10 % apple juice. Results: One-time ingestion of apple juice significantly decreased the area under the plasma concentration-time curve (AUC0-24) for (R)- and (S)-fexofenadine by 49 and 59 %, respectively, and prolonged the time to reach the maximum plasma concentration (t max) of both enantiomers (P∈<∈0.001). Although apple juice greatly reduced the amount of (R)- and (S)-fexofenadine excretion into urine (Ae0-24) by 54 and 58 %, respectively, the renal clearances of both enantiomers were unchanged between the control and apple juice phases. For in vitro uptake studies, the uptake of both fexofenadine enantiomers into OATP2B1 complementary RNA (cRNA)-injected oocytes was significantly higher than that into water-injected oocytes, and this effect was greater for (R)-fexofenadine. In addition, apple juice significantly decreased the uptake of both enantiomers into OATP2B1 cRNA-injected oocytes. Conclusions: These results suggest that OATP2B1 plays an important role in the stereoselective pharmacokinetics of fexofenadine and that one-time apple juice ingestion probably inhibits intestinal OATP2B1-mediated transport of both enantiomers. In addition, this study demonstrates that the OATP2B1 inhibition effect does not require repeated ingestion or a large volume of apple juice. © 2014 Springer-Verlag.
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The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers
Satoshi Yamada, Hideo Shiohira, Norio Yasui-Furukori, Tomonori Tateishi, Yumiko Akamine, Tsukasa Uno
European Journal of Clinical Pharmacology ( Springer Science and Business Media LLC ) 69 ( 7 ) 1423 - 1428 2013年07月
研究論文（学術雑誌）
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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.
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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）
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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）
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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）
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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.
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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.
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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。
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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）
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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.
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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。
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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）