研究等業績 - 原著論文 - 赤嶺 由美子
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Akamine Y.
Journal of Clinical Pharmacy and Therapeutics ( Journal of Clinical Pharmacy and Therapeutics ) 46 ( 5 ) 1312 - 1318 2021年
研究論文（学術雑誌）
What is known and objective: The schizophrenia guidelines in Japan and many other countries describe clozapine as the first-choice drug for patients with treatment-resistant schizophrenia. However, there have been no reports to date on the effects of the introduction of clozapine on the prescription of other antipsychotics and concomitant drugs. Methods: In this study, we retrospectively investigated the prescription of antipsychotics and concomitant drugs before vs 6 months after and 12 months after switching to clozapine. Results and discussion: Clozapine was introduced to 62 patients with treatment-resistant schizophrenia, and 51 patients continued on clozapine therapy. Six months after switching to clozapine, there was a significant decrease in the mean number of antipsychotic drugs (2.04 ± 0.75 vs 1.10 ± 0.30: p < 0.001) and in the mean chlorpromazine equivalent value (1024 ± 73 mg/day vs 781 ± 391 mg/day: p < 0.001) compared to before switching. Moreover, antipsychotic monotherapy increased from 24% to 90% after switching to clozapine. In addition, the number of concomitant benzodiazepines, anti-parkinson drugs and antidepressants also significantly decreased 6 and 12 months after switching to clozapine (p < 0.001 for benzodiazepines and anti-parkinson drugs, and p < 0.05 for antidepressants). What is new and conclusion: Our study suggests that switching to clozapine may reduce the use of antipsychotic combination therapy, and may also reduce the number of concomitant drugs.
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Sakamoto S.
Investigational New Drugs ( Investigational New Drugs ) 38 ( 6 ) 1687 - 1695 2020年12月
研究論文（学術雑誌）
ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.
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加藤 駿介, 赤嶺 由美子, 石川 誠, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 3 ) 153 - 158 2020年12月
研究論文（学術雑誌）
術前3ヵ月以上前から睡眠薬を定期内服していた白内障手術患者28名(男性12名、女性16例、平均年齢69±13歳)を対象として、術後の睡眠薬処方状況を後方視的に調査し、白内障術後の睡眠薬の適正使用について検討した。術後に処方された睡眠薬のジアゼパム換算値の増減を評価した。その結果、ジアゼパム換算値は年齢や併用薬剤にかかわらず、術後1ヵ月以降より減少し、術後6ヵ月の時点で有意な減少が確認された。臨床検査値や併用薬剤数、副腎皮質ステロイド内服患者のヒドロコルチゾン換算値は睡眠薬処方の変化に影響を及ぼす有意な要因ではなかった。本研究より、白内障手術患者においては術後6ヵ月以降に睡眠薬を減薬できる可能性が示唆されたが、減薬・休薬のタイミングは難しく、患者の睡眠状況を確認し、長期的なモニタリングを経て減薬を提案することが望ましい。
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インドメタシンが未熟児動脈管開存症患者の尿量へ及ぼす影響と血清電解質の変化
大久保 翔, 赤嶺 由美子, 安達 裕行, 高橋 勉, 三浦 昌朋
医薬品相互作用研究 ( (一社)医薬品相互作用研究会 ) 44 ( 2 ) 96 - 101 2020年09月
研究論文（学術雑誌）
インドメタシン(IND)が未熟児の尿量へ与える影響、尿量減少の発生時期とその経過、IND投与後の血清電解質の変化を後方視的に検討した。在胎37週未満の早産児のうち、動脈管開存症(PDA)と診断された患者でINDを投与した24名をIND群、PDAと診断されたが早急なIND投与の必要性はないと判断され経過観察となった13名を対照群とした。IND群の尿量変化率の中央値は-38.5%であったのに対して、対照群は-10.0%と有意にIND群で尿量減少がみられた。水分率が90mL/kg/day未満に調整されている患者はIND群では24名中18名、対照群は13名中5名に認められており、IND群で有意に多くみられた。また、IND群では血清ナトリウム(Na)値が基準値以下まで低下したのは24名中11名、対照群では13名中1名とIND群で有意に多かった。血清カリウム値が基準値以上になったのはIND群で1名のみであった。IND投与が尿量へ与える影響は大きく、INDによる尿量減少は高い確率で投与後24時間以内に発生し、さらに希釈性の低Na血症を引き起こしていた。
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Sato S.
Pharmacological Reports ( Pharmacological Reports ) 72 ( 3 ) 622 - 630 2020年06月
研究論文（学術雑誌）
Background: The purpose of this study was to evaluate the effects of concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein (LDL) cholesterol by the mammalian target of rapamycin (mTOR) inhibitor everolimus and their effects on genetic polymorphisms in the PCSK9 and mTORC1 genes in 53 renal transplant recipients. Methods: Prior to and on day 15 after everolimus administration, the concentrations of everolimus in blood and PCSK9 and LDL cholesterol in plasma were evaluated. Additionally, mTORC1 (rs2536T>C and rs2295080T>G) and PCSK9 (rs505151G>A, rs562556G>A, and rs11593680C>T) polymorphisms were analyzed. Results: Mean PCSK9 plasma concentrations on day 15 after everolimus treatment were significantly higher than those before treatment (295 versus 214 ng/mL, respectively; p = 0.004). Significant correlations between the area under the blood concentration–time curves (AUC)0–12 on day 15 of everolimus treatment and the change rate in PCSK9 concentrations were found (r = 0.316, p = 0.021). However, there were no significant correlations between the change rate in PCSK9 and LDL cholesterol concentrations. The change rate in PCSK9 concentrations by everolimus treatment was significantly greater in patients with the mTORC1 rs2295080G allele than the T/T genotype (p = 0.006); however, there were no significant differences between PCSK9 rs505151G>A and rs11583680C>T genotypes. In multivariate analyses, patients with mTORC1 rs2295080G (p = 0.010), higher everolimus AUC0–12 (p = 0.006), and female sex (p = 0.029) showed higher change rates of PCSK9 following everolimus therapy. Conclusions: Administration of everolimus significantly elevated plasma PCSK9 concentrations, potentially causing everolimus-induced hyperlipidemia.
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Ohkubo S.
Journal of Chromatographic Science ( Journal of Chromatographic Science ) 58 ( 10 ) 915 - 921 2020年
研究論文（学術雑誌）
Abstract
Here, we developed a novel high-performance liquid chromatography (HPLC) method for quantification of perampanel in clinical practice and investigated the relationships between the plasma concentrations of perampanel obtained by this HPLC method and the CYP3A4*1G polymorphism. The developed HPLC method was validated based on US Food and Drug Administration. The developed HPLC method could be performed with a plasma volume of only 200 μL and had a limit of quantification (LOQ) of 2.5 ng/mL. The coefficients of variation (CVs) for intra- and inter-day assays were less than 10.4 and 7.2%, respectively, and the accuracy was &lt;2.4% for both assays. A total of 12 patients who received 2 mg perampanel had C0 values ranging from 70.5 to 451 ng/mL, and the CV showed a large variation of 51.4%. No correlations were observed between the dose-adjusted C0 and the CYP3A4*1G polymorphism. This method was superior to previously reported methods in terms of plasma volume and LOQ and was clinically applicable. Perampanel showed high variations in individual plasma concentrations; however, individual differences could not be predicted from analysis of the CYP3A4*1G polymorphism before perampanel administration. Therefore, after beginning perampanel treatment, the dose should be determined based on the observed plasma concentration. -
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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【さまざまな背景のある患者にどうする?-リアルワールドの薬物療法】肝疾患・心疾患の精神科薬物療法
赤嶺 由美子, 古郡 規雄, 宇野 司
臨床精神薬理 ( (株)星和書店 ) 22 ( 12 ) 1175 - 1183 2019年12月
研究論文（学術雑誌）
向精神薬の多くは肝臓にて代謝を受け、排泄されるため、肝疾患がある場合、代謝活性低下に伴い、薬剤の血中濃度が上昇し、副作用発現のリスクが高まる。さらに、心疾患時においても、心拍出量の低下に伴い、薬剤のクリアランスが低下することが報告されている。しかしながら、臨床現場においては肝疾患ならびに心疾患があっても、向精神薬の投与を必要とする場合は多く存在する。さらに、向精神薬の多くは薬物代謝酵素や薬物輸送トランスポータの基質または阻害剤となり、考慮しなければならない薬物相互作用も多い。そこで本稿では肝疾患・心疾患時の精神科薬物療法について各薬剤の特性をまとめ、薬物動態の観点から違いを理解し、臨床にて留意すべきポイントを中心に述べる。(著者抄録)
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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）