研究等業績 - 原著論文 - 赤嶺 由美子
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Abumiya M.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 2 ) 382 - 387 2020年
研究論文（学術雑誌）
What is known and objective: The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0), low-density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. Methods: Plasma concentrations of nilotinib and PCSK9 were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively. Results and discussion: LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P =.019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut-off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P =.043); however, there were no differences in mean nilotinib C0. What is new and conclusion: Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib-induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.
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Yagishita H.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 44 ( 6 ) 977 - 980 2019年12月
研究論文（学術雑誌）
What is known and objective: Lenvatinib inhibits CYP2C8. (S)-Warfarin is metabolized to (S)-7-hydroxywarfarin by CYP2C9 and (S)-4'-hydroxywarfarin by CYP2C8. Here, we report drug interactions between warfarin and lenvatinib in a patient with CYP2C9*1/*3. Case summary: The patient was administered warfarin. His international normalized ratio (INR) was 1.92 before lenvatinib administration. On day 8 after beginning 12 mg/day lenvatinib, plasma trough concentrations of lenvatinib and (S)-warfarin were 33.3 ng/mL and 0.67 μg/mL, respectively. On day 10, his INR increased to 3.48. What is new and conclusion: Lenvatinib-dependent (S)-warfarin inhibition could involve CYP2C9 and CYP2C8. After initiating warfarin plus lenvatinib, INR assays are necessary.
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熊谷 優, 赤嶺 由美子, 安倍 明, 和田 優貴, 戸沢 智樹, 笹嶋 素子, 熊谷 聡, 橋本 学, 三浦 昌朋
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 55 ( 7 ) 805 - 812 2019年07月
研究論文（学術雑誌）
シスプラチンの腎毒性発現リスクはカルシウム拮抗薬(calcium channel blocker:以下、CCB)との併用によって増強されることが動物にて報告されているが、ヒトでの報告は少ない。今回、シスプラチン投与食道がん患者の腎機能に及ぼす降圧剤の影響を調査した。食道がん放射線化学療法施行患者のうち、降圧剤併用群42名、非併用群71名を調査対象とした。CCB併用群およびアンジオテンシンII受容体拮抗薬(angiotensin II receptor blocker:以下、ARB)あるいはアンジオテンシン変換酵素阻害薬(angiotensin-converting-enzyme inhibitor:以下、ACEI)併用群は非併用群と比べて急性腎障害(acute kidney injury:以下、AKI)の発現頻度が有意に高く(それぞれp=0.001、p=0.011)、またAKI発現時期はシスプラチン治療開始後7日目で最も高かった。シスプラチンと降圧剤の併用によって、AKI発現リスクが高まる可能性が示唆された。シスプラチン治療開始前にCCB、ARBおよびACEI以外の薬剤への変更を提案することが望まれるが、降圧剤使用継続の際は早期からの血液検査のモニタリングが必要と考える。(著者抄録)
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Kobayashi T.
Medical Oncology ( Medical Oncology ) 36 ( 6 ) 2019年06月
研究論文（学術雑誌）
Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration–time curve (AUC0–24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0–24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0–24 in 1236C>T and 2677G>A/T polymorphisms. AUC0–24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0–24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0–24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.
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Drug-drug interactions of P-gp substrates unrelated to CYP metabolism
Akamine Y.
Current Drug Metabolism ( Current Drug Metabolism ) 20 ( 2 ) 124 - 129 2019年
研究論文（学術雑誌）
Background:
Recent US Food and Drug Administration (FDA) draft guidance on pharmacokinetic drugdrug interactions (DDIs) has highlighted the clinical importance of ABC transporters B1 or P-glycoprotein (P-gp), hepatic organic anion-transporting polypeptide transporters and breast cancer resistant protein because of their broad substrate specificity and the potential to be involved in DDIs. This guidance has indicated that digoxin, dabigatran etexilate and fexofenadine are P-gp substrate drugs and has defined P-gp inhibitors as those that increase the AUC of digoxin by ≧1.25-fold in clinical DDI studies. However, when substrate drugs of both CYPs and P-gp are involved in DDIs, it remains that the mechanisms of DDIs will be quite ambiguous in assessing how much the CYPs and/or drug transporters partially contribute to DDIs.
Objective:
Since there are no detailed manuscripts that summarizes P-gp interactions unrelated to CYP metabolism, this article reviews the effects of potent P-gp inhibitors and P-gp inducers on the pharmacokinetics of P-gp substrate drugs, including digoxin, talinolol, dabigatran etexilate, and fexofenadine in human studies. In addition, the present outcome were to determine the PK changes caused by DDIs among P-gp substrate drugs without CYP metabolism in human DDI studies.
Conclusion:
Our manuscript concludes that the PK changes of the DDIs among P-gp drugs unrelated to CYP metabolism are less likely to be serious, and it appears to be convincing that the absences of clinical effects caused to the PK changes by the P-gp inducers is predominant compared with the excessive effects caused to those by the P-gp inhibitors. -
Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 43 ( 5 ) 675 - 681 2018年10月
研究論文（学術雑誌）
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未熟児動脈管開存症へのインドメタシン投与が血糖値に与える影響とリスク因子に関する調査
大久保 翔, 赤嶺 由美子, 安達 裕行, 高橋 勉, 三浦 昌朋
日本病院薬剤師会雑誌 ( (一社)日本病院薬剤師会 ) 54 ( 6 ) 705 - 708 2018年06月
研究論文（学術雑誌）
本研究はインドメタシン投与後の未熟児の血糖変動と血糖低下への臨床的介入について調査し、さらに血糖値変化に影響を及ぼす要因について検討した。インドメタシン初回投与の未熟児22名を対象とし、投与前後の血糖値、糖質補充の有無について後方視的に調査した。血糖変化率に影響を及ぼす因子として日齢、在胎週数、出生体重、初回投与量との関連を検討した。インドメタシン投与時に糖質補充を追加していない14例中4例に血糖低下、4例に血糖上昇(それぞれ、変化率の中央値:-31.1%および26.4%)が観察された。4例にインドメタシンによる低血糖予防として追加の糖質補充が行われており、そのなかに血糖低下を来す患児はいなかった。血糖変化率と相関のある因子は観察されなかった。血糖低下の予防として糖質補充の有用性が示されたが、血糖変化は低下のみならず上昇する患者もいることから、投与前後は細めな血糖値の測定が求められる。(著者抄録)
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Comparison electrochemiluminescence immunoassay and latex agglutination turbidimetric immunoassay for evaluation of everolimus blood concentrations in renal transplant patients.
Akamine Y, Sato S, Kagaya H, Ohkubo T, Satoh S, Miura M.
Journal of Clinical Pharmacy and Therapeutics 2018年04月 [査読有り]
研究論文（学術雑誌） 国内共著
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An update on the clinical pharmacokinetics of fexofenadine enantiomers
Akamine Y.
Expert Opinion on Drug Metabolism and Toxicology ( Expert Opinion on Drug Metabolism and Toxicology ) 14 ( 4 ) 429 - 434 2018年04月
研究論文（学術雑誌）
Introduction: Fexofenadine is administered as a racemic mixture of (R)- and (S)-enantiomers. The plasma concentrations of (R)-fexofenadine in humans are about 1.5-fold higher than those of the (S)-enantiomer. Such differences in the pharmacokinetics between fexofenadine enantiomers are likely to be dependent on stereoselectivity for affinity to drug-transporters. Areas covered: This review focuses on elucidation of differences in clinical pharmacokinetics between fexofenadine enantiomers. Expert opinion: Differences in pharmacokinetics between fexofenadine enantiomers were caused by organic anion transporting polypeptide (OATP) 2B1, with a minor contribution from P-glycoprotein (P-gp). In vitro studies using OATP2B1 cRNA showed that (R)-fexofenadine uptake into oocytes is greater than (S)-enantiomer uptake. P-gp inducers, carbamazepine, and inhibitors such as itraconazole and verapamil show greater effects on the pharmacokinetics of (S)-fexofenadine. Apple juice and grape fruit juice, OATP2B1 inhibitors, significantly decrease the exposure of both fexofenadine enantiomers, particularly the (S)-enantiomer, but do not change the t1/2. Rifampicin significantly increases plasma concentrations of both enantiomers through inhibition of OATP1B3, whereas enantioselectivity of fexofenadine uptake by OATP1B3-expressing cells has not been observed. Combinations of multiple transporters such as OATP2B1 and P-gp facilitate enantioselective disposition of fexofenadine. Drug-transporters appear to be capable of chiral discrimination for transport of drugs with an asymmetric center.
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 43 ( 2 ) 181 - 188 2018年04月
研究論文（学術雑誌）
What is known and objective: The anti-tacrolimus antibodies used in commercial immunoassay methods have cross-reactivity with tacrolimus metabolites. The aim of this study was to investigate differences in the effects of CYP3A5 polymorphism on tacrolimus concentrations obtained by four immunoassay methods in renal transplant patients. Methods: Samples (n = 508) were evaluated using four immunoassays (chemiluminescence enzyme immunoassay [CLIA], affinity column-mediated immunoassay [ACMIA], electrochemiluminescence immunoassay [ECLIA] and latex agglutination turbidimetric immunoassay [LTIA]). Results: Bland-Altman plots showed average biases of −0.12 (±1.96 SD: −1.30-1.05) ng/mL for CLIA, −0.30 (−1.59-1.00) ng/mL for ECLIA, 0.42 (−1.21-2.05) ng/mL for ACMIA and 1.88 (−0.51-4.28) ng/mL for LTIA, when considering the mean of the three immunoassays (CLIA, ECLIA and ACMIA). In multiple regression analysis, the difference (CLIA—mean) was affected by haematocrit levels. Differences in ECLIA were correlated with red blood cell counts. For LTIA, CYP3A5 genotype and haematocrit levels were identified as independent predictors for this bias. What is new and conclusion: The results obtained by CLIA, ECLIA and ACMIA were not affected by CYP3A5 polymorphism. However, in LTIA, CYP3A5*1/*3-derived data exhibited an inverse relationship in Bland-Altman analysis (slope: −0.0824). Higher cross-reactivity with 12-hydroxy tacrolimus at lower concentrations may occur in patients with the CYP3A5*1/*3 genotype. Because patients with the CYP3A5*1 allele identified using LTIA may show higher blood concentrations of tacrolimus at lower target concentrations, for example 3.0 ng/mL, compared with other immunoassay methods, there is a need for sufficient consideration of the interpretation of values measured by LTIA.
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Kagaya H.
International Journal of Molecular Sciences ( International Journal of Molecular Sciences ) 19 ( 3 ) 882 - 882 2018年03月
研究論文（学術雑誌）
While tacrolimus and everolimus have common metabolic pathways through CYP3A4/5, tacrolimus is metabolized solely by CYP3A4 in recipients with the CYP3A5*3/*3. The purpose of this study was to evaluate how the area under the blood concentration-time curves (AUC) of tacrolimus could be predicted based on CYP3A5 genotype and the AUC of everolimus in renal transplant patients taking both drugs. The dose-adjusted AUC (AUC/D) of tacrolimus and everolimus were calculated at one month and one year after transplantation. Significant correlations between the AUC/D of tacrolimus and everolimus were found for patients with the CYP3A5*1 allele or CYP3A5*3/*3 at both one month and one year. At both stages, the determination coefficients were higher and the slopes of regression equations were larger for patients with CYP3A5*3/*3 compared to the CYP3A5*1 allele. A good correlation between single doses of tacrolimus and everolimus was found for CYP3A5*3/*3 patients at 1 year after transplantation (r = 0.794, p < 0.001). The variability of the AUC0–24/D of tacrolimus for each CYP3A5 genotype could be predicted based on the AUC0–12/D of everolimus. Clinicians may be able to comprehensively carry out the dose adjustments of tacrolimus and everolimus based on relationship with AUCs of both drugs in each CYP3A5 genotype.
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Akamine Y.
Annals of Clinical Biochemistry ( Annals of Clinical Biochemistry ) 54 ( 6 ) 677 - 685 2017年11月
研究論文（学術雑誌）
Background
This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C<sub>0</sub>) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia.
Methods
Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction.
Results
The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C<sub>0</sub>/dose (C<sub>0</sub>/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C<sub>0</sub>/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C<sub>0</sub>/D ratios of clozapine ( R<sup>2 </sup>= 0.139, P = 0.016).
Conclusions
Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient’s ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure. -
Effects of selective serotonin reuptake inhibitors on the pharmacokinetics of proton pump inhibitors
Tsukasa Uno, Yumiko Akamine, Norio Yasui-Furukori, Takayuki Hirano
Neuropsychiatry (London) 7 ( 4 ) 393 - 397 2017年
研究論文（学術雑誌）
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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）