Faculty Profiles - ARIYOSHI Noritaka

Papers - ARIYOSHI Noritaka

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Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation. Reviewed International journal

Hiroyoshi Nakamura, Takeyuki Sato, Kenji Okada, Go Miura, Noritaka Ariyoshi, Kazuyoshi Nakazawa, Mitsukazu Kitada

Therapeutic drug monitoring 30 ( 1 ) 75 - 83 2008.2

Language：English Publishing type：Research paper (scientific journal)

The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.

DOI： 10.1097/FTD.0b013e3181621cde

医薬品数量管理システム構築と医薬品購入費および業務効率に対する効果

大久保正人, 増田和司, 長谷川敦, 中村貴子, 野口昇, 中村裕義, 中澤一純, 有吉範高, 北田光一

日本病院薬剤師会雑誌 44 ( 2 ) 233 - 236 2008.2

Language：Japanese Publisher：(一社)日本病院薬剤師会

医薬分業の進展により院内で調剤される医薬品数量は減少したが、投与日数制限が原則撤廃されたために一度に処方される数量は増加しており、調剤室に置く医薬品数量の調整が新たな課題となっている。そこで、本研究では調剤室の医薬品数量の適正化を目的として、病院情報システムのデータを利用した医薬品請求システムの構築を試みた。まず、処方オーダリングシステムのデータから対象医薬品の処方量を医薬品別・月別に集計し、適正な一回請求量の設定と不動医薬品の選別化を行った。次に、処方が低頻度な高額医薬品の管理のために、患者の次回来院予定日を電子カルテから検索するシステムを構築した。これらのシステム稼動前後で、年度末棚卸金額は40.4%減少、特に外用剤では54.8%と著しく減少した。一方で、臨時発注件数には顕著な増加は認められず、今回の取り組みが在庫適正化に寄与したと考えられた。(著者抄録)

Relationship between Kaposi's varicelliform eruption in Japanese patients with atopic dermatitis treated with tacrolimus ointment and genetic polymorphisms in the IL-18 gene promoter region. Reviewed International journal

Kouji Osawa, Takafumi Etoh, Noritaka Ariyoshi, Itsuko Ishii, Michteru Ohtani, Satoru Kariya, Katsuyoshi Uchino, Mitsukazu Kitada

The Journal of dermatology 34 ( 8 ) 531 - 6 2007.8

Language：English Publishing type：Research paper (scientific journal)

Kaposi's varicelliform eruption is the most important problem in treating patients with atopic dermatitis (AD) with tacrolimus ointment. It has been considered that Kaposi's varicelliform eruption occurs due to decreased levels of interleukin (IL)-18. The aim of this study was to examine the relationship between Kaposi's varicelliform eruption and genetic polymorphisms in the IL-18 gene. IL-18 gene promoter polymorphisms were analyzed in 21 AD patients treated with tacrolimus ointment and in 100 healthy volunteers. Six AD patients with Kaposi's varicelliform eruption during the treatment with tacrolimus ointment showed significantly higher frequency in G-to-C mutations at the IL-18 gene promoter region -137 compared with 15 AD patients without Kaposi's varicelliform eruption. The 15 AD patients without Kaposi's varicelliform eruption as well as 100 healthy volunteers did not have mutations of G-to-C at the IL-18 gene promoter region -137. These results suggest that the onset of Kaposi's varicelliform eruption following the treatment with tacrolimus ointment is associated with the mutation of G-to-C in the IL-18 gene promoter region -137, and that caution is required when using tacrolimus ointment for treating AD patients with this mutation.

院外処方内容に関するチェックシート機能の利用とデータベース構築

長谷川敦, 小林えり, 近藤夏未, 木村真春, 松島徹, 中村貴子, 中澤一純, 有吉範高, 北田光一

日本病院薬剤師会雑誌 43 ( 8 ) 1087 - 1089 2007.8

Language：Japanese Publisher：(一社)日本病院薬剤師会

千葉大学医学部附属病院(以下、当院)薬剤部では、当院における院内・院外処方せんについて相互作用の可能性のある医薬品が併用された場合や複数の診療科から重複して薬が処方された場合に、チェックシートが出力されるシステムを利用している。しかし、このチェックシートに基づいて疑義照会を行う際、過去に問い合わせた内容であるか否かが判断できないため、処方鑑査の質は向上したものの、業務の効率化という点では問題を残していた。そこで今回、院外処方に対するチェックシートに関する照会事項をデータベース化した。その結果、データベースを利用することで同一内容の疑義照会を回避でき、問い合わせを行うか否かの判断も容易となった。また、チェックシートを基に疑義照会を行うことで処方内容に変更が生じ、その後のチェックシートの出力枚数が減少し、さらには保険薬局からの問い合わせの減少にもつながり、業務の効率化に貢献できることがわかった。(著者抄録)

Identification and partial characterization of a novel CYP2C9 splicing variant encoding a protein lacking eight amino acid residues. Reviewed International journal

Noritaka Ariyoshi, Yoko Shimizu, Yukari Kobayashi, Hiroyoshi Nakamura, Hiromitsu Nakasa, Kazuyoshi Nakazawa, Itsuko Ishii, Mitsukazu Kitada

Drug metabolism and pharmacokinetics 22 ( 3 ) 187 - 94 2007.6

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

CYP2C9 is known as an enzyme responsible for the metabolism of various clinically important drugs. Recently, we cloned a cDNA corresponding to a CYP2C9 splicing variant (SV), which seemed to have an open reading frame of a protein with 482 amino acid residues. To investigate whether or not the SV can be translated as a functionally active protein, we expressed the CYP2C9SV in insect cells, and spectrophotometric and enzymatic properties were characterized. The CYP2C9SV protein showed a typical reduced CO-difference spectrum, indicating that the translated protein binds a heme moiety. However, CYP2C9SV did not metabolize tolbutamide or diclofenac at all, suggesting that the SV protein appeared to lack the ability to catalyze reactions mediated by CYP2C9. Although the CYP2C9SV mRNA was detected in all human liver samples examined in this study by real-time PCR, the level was generally low, ranging between 0.7 and 9.6% of the normal CYP2C9 mRNA. These results suggest that the CYP2C9SV protein is unlikely to contribute to CYP2C9 activities, although it appears to be expressed in most individuals.

Helices F-G are important for the substrate specificities of CYP3A7 Reviewed

Nao Torimoto, Itsuko Ishii, Ken-Ichi Toyama, Masayuki Hata, Kanako Tanaka, Hitoshi Shimomura, Hiroyoshi Nakamura, Noritaka Ariyoshi, Shigeru Ohmori, Mitsukazu Kitada

DRUG METABOLISM AND DISPOSITION 35 ( 3 ) 484 - 492 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone ( DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16 alpha-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu210 to Glu279 were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16 alpha-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.

DOI： 10.1124/dmd.106.011304

Theoretical calculation of triazolam hydroxylation and endogenous steroid inhibition in the active site of CYP3A4. Reviewed International journal

Nao Torimoto, Itsuko Ishii, Masayuki Hata, Yukari Kobayashi, Hiroyoshi Nakamura, Noritaka Ariyoshi, Mitsukazu Kitada

Biochimica et biophysica acta 1774 ( 2 ) 223 - 32 2007.2

Language：English Publishing type：Research paper (scientific journal)

CYP3A4 has unusual kinetic characteristics because it has a large active site. CYP3A4 produced more 4-hydroxytriazolam than alpha-hydroxytriazolam at concentrations of more than 60 muM triazolam, and different steroids had different inhibitory effects on the system. To clarify these interesting observations, the interactions between substrate and substrate/steroid were investigated by theoretical calculations. When two triazolam molecules were docked into the active site, the distance between the O-atom and the 4-hydroxylated site was less than the distance to the alpha-hydroxylated site because of interaction between the two triazolam molecules. Estradiol inhibited both alpha- and 4-hydroxytriazolam formation by 50%. Dehydroepiandrosterone (DHEA) inhibited alpha-hydroxylation more than 4-hydroxytriazolam formation, whereas aldosterone had no effect. When one triazolam molecule and one steroid molecule were simultaneously docked, estradiol increased the distance between the O-atom and the two hydroxylated sites, DHEA only increased the distance between the O-atom and alpha-hydroxylated site, and aldosterone did not change the distances. The relevant angles of Fe-O-C in the hydroxylated site of triazolam also widened, together with increased distance. These findings indicate that formation of a substrate and substrate/effector complex in the active site may be a factor for determining the enzyme kinetic parameters of CYP3A4.

資料に基づく後発医薬品の評価プラバスタチンナトリウムおよびシンバスタチン製剤の比較

久保さやか, 中澤一純, 長谷川敦, 岡田賢二, 有吉範高, 北田光一

日本病院薬剤師会雑誌 42 ( 2 ) 219 - 223 2006.2

Language：Japanese Publisher：(一社)日本病院薬剤師会

資料に基づく後発医薬品の評価としてHMG-CoA還元酵素阻害剤のプラバスタチンナトリウムとシンバスタチン製剤を比較した.方法は,プラバスタチンナトリウム製剤22製品およびシンバスタチン製剤12製品の添付文書,インタビューフォームを用いて情報の評価を行なった.1)添付文書,インタビューフォーム記載事項はいずれも製剤間で異なっており,先発品は全ての調査項目について記載されていたが,後発品では吸収速度定数(Ka),消失速度定数(Ke),クリアランス(CL),分布容積(Vd)が記載されているのはプラバスタチンナトリウムで4割以下,シンバスタチンで5割以下であった.2)添加物では,両製剤とも9割以上の後発品で記載があったが,記載のないもの,製剤により添加物が違うものを認めた.3)安全性では,先発品ほど詳細な検討が行われていない後発品が過半数を占め,条件設定も製剤間で異なり,資料請求電話番号なしが7割を占めていた.4)単回投与での血中濃度推移は製剤間で大きなばらつきを認めた.以上,先発品も含め,情報提供のあり方に課題があると考えられた

CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes Reviewed

H Nakamura, N Ariyoshi, K Okada, H Nakasa, K Nakazawa, M Kitada

CURRENT DRUG METABOLISM 6 ( 5 ) 469 - 480 2005.10

Language：English Publisher：BENTHAM SCIENCE PUBL LTD

Granisetron, a potent 5-HT3 receptor antagonist, has been reported to be mainly metabolized to 7-hydroxygranisetron and a lesser extent to 9'-desmethylgranisetron in humans. A previous study indicated that cytochrome P450 (CYP)3A4 is a major catalyst of 9'-demethylation, although the major CYP isoform(s) responsible for 7-hydroxylation are unknown. To clarify granisetron 7-hydroxylase, the in vitro metabolism of granisetron using expressed human CYPs and human liver microsomes was investigated. 7-Hydroxygranisetron was produced almost exclusively by CYP1A1, while, apparently, 9'-desmethylgranisetron was preferentially produced by CYP3A4. Marked inter-individual differences in the ratio of the formation of 7-hydroxygranisetron and 9'-desmethylgranisetron in human liver microsomes was observed. Granisetron 7-hydroxylase activity was strongly correlated with benzo[a]pyrene 3-hydroxylase activity (p < 0.0001), but not with testosterone 6 beta-hydroxylase activity in human liver microsomes. Furthermore, an anti-human CYP I A I antibody completely inhibited 7-hydroxylation in human liver microsomes, however, the reaction was not inhibited at all by an anti-CYP3A4 antibody. On the other hand, granisetron 9'-demethylase activity correlated significantly not only with testosterone 6 beta-hydroxylase activity (p < 0.0001) but also with benzo[a]pyrene 3-hydroxylase activity (p < 0.01). Consistent with this, both the anti-CYP1A1 and anti-human CYP3A4 antibodies inhibited the 9'-demethylase activity. These data indicate that CYP1A1 is a major enzyme responsible for the metabolism of granisetron via a main 7-hydroxylation pathway and an alternative 9'-demethylation route. This is the first report demonstrating the substantial contribution of CYP1A1 to the metabolism of a drug, although its role in the metabolism of environmental compounds is well established.

造血幹細胞移植施行患者におけるフルコナゾール血中濃度モニタリングの有用性に関する検討

鈴木貴詞, 岡田賢二, 中村裕義, 有吉範高, 中澤一純, 北田光一

TDM研究 22 ( 4 ) 322 - 327 2005.10

Language：Japanese Publisher：(一社)日本TDM学会

造血幹細胞移植(HSCT)施行患者に対し,フルコナゾール(FLCZ)は深在性真菌症予防の目的で高用量が長期間投与される.HSCT施行患者では免疫抑制剤など腎毒性の高い薬物が投与されるため,腎排泄型薬物であるFLCZの血中濃度の上昇を来し,副作用を生じる恐れがある.そこで,HSCT施行患者を対象として血漿中FLCZ濃度の測定を行い,FLCZ血中濃度モニタリングの有用性について検討を行った.今回対象とした7名の患者のいずれにおいても,腎機能低下に伴うと考えられる血漿中FLCZ濃度の上昇が認められたが,その上昇の程度は患者間で大きく異なっていた.現在FLCZの添付文書には,クレアチニンクリアランスが50ml/min以下の患者には投与量を半減するように記載されているが,本方法では,患者個々に対する至適投与量の設定は困難と推察された.したがって,腎機能の低下が頻発するHSCT施行患者におけるFLCZ血中濃度モニタリングの施行は適正使用の観点から望ましいと考えられた(著者抄録)

Inhibitory effects of nicardipine to cytochrome P450 (CYP) in human liver microsomes. Reviewed

Katsunori Nakamura, Noritaka Ariyoshi, Takafumi Iwatsubo, Yasuhisa Fukunaga, Saburou Higuchi, Kunio Itoh, Noriaki Shimada, Kazuo Nagashima, Tsuyoshi Yokoi, Koujirou Yamamoto, Ryuya Horiuchi, Tetsuya Kamataki

Biological & pharmaceutical bulletin 28 ( 5 ) 882 - 5 2005.5

Language：English Publishing type：Research paper (scientific journal)

To anticipate drug-drug interactions by nicardipine in vivo, cytochrome P450 (CYP) forms responsible for the metabolism of nicardipine and inhibition of CYP-dependent drug metabolism by nicardipine were investigated. Microsomes of human B-lymphoblastoid cells expressing each human CYP form were used for the metabolism of nicardipine. Inhibitory effects of nicardipine on drug metabolism were studied using human liver microsomes. CYP2C8, CYP2D6 and CYP3A4 were identified as major CYP forms for the metabolism of nicardipine in human liver microsomes. Nicardipine strongly inhibited two-pathways of triazolam hydroxylation both catalyzed by CYP3A4. Comparison of three Ca(2+) antagonists, nicardipine, nifedipine, and diltiazem revealed that only nicardipine showed such a strong inhibitory potency on the typical CYP2D6-catalyzed drug metabolism. Furthermore, nicardipine inhibited other reactions catalyzed by CYP1A, CYP2A6, CYP2C8, CYP2C9 and CYP2C19 with K(i) values ranging from 1.1 to 29.4 microM. In conclusion, nicardipine was a relatively potent inhibitor of human CYP2D6, CYP3A4 and CYP2C (especially for CYP2C8 and CYP2C19) in vitro, suggesting that drug-drug interactions between nicardipine and other drugs metabolized mainly by these CYP forms appear to occur in vivo.

血液透析患者におけるアルベカシンの投与設計

岡田賢二, 鈴木貴詞, 中村裕義, 石川耕, 有吉範高, 中澤一純, 齋藤康, 北田光一

TDM研究 22 ( 1 ) 27 - 33 2005.1

Language：Japanese Publisher：(一社)日本TDM学会

45歳男.2型糖尿病,慢性腎不全,右下腿潰瘍,MRSA骨髄炎であった.慢性腎不全による浮腫を軽減する目的で,週3回,1回4時間の血液透析(HD)を施行した.右下腿潰瘍部よりMRSAおよびP.aeruginosaを検出した.HDスケジュールを考慮したアルベカシン(ABK)の投与設計を試みた.HD施行3時間前にABKを投与することによって,ピーク濃度を約9〜10μg/mlで数時間持続させ,かつトラフ濃度を2μg/ml付近まで低下させることを可能にした.しかし,体温とCRPの低下は認めたが,MRSAの消失には至らなかった

心臓血管外科手術後患者に対するアンジオテンシン変換酵素阻害薬およびアンジオテンシンII受容体拮抗薬使用成績

公手妙, 中村貴子, 仲佐啓詳, 石井晃, 中澤一純, 有吉範高, 今牧瑞浦, 宮崎勝, 北田光一

日本病院薬剤師会雑誌 40 ( 11 ) 1425 - 1427 2004.11

Language：Japanese Publisher：(一社)日本病院薬剤師会

アンジオテンシン変換酵素阻害薬(ACEI)およびアンジオテンシンII受容体拮抗薬(ARB)は,高カリウム(K)血症をひき起こすことが知られ,K保持性利尿薬との併用や腎機能低下患者に対する使用では,高K血症を助長させる危険性があり注意が必要である.今回,心臓血管外科手術後の患者におけるACEIあるいはARBの使用と高K血症との関連性について検討した.ACEIおよびARB使用による明らかなK値上昇傾向は認めず,電解質変動への影響が少ない薬剤であることが示唆された.しかし,高K値を示した患者を個々に評価すると,これら薬剤による高K血症の発現が疑われる症例もあり,使用時には十分な注意が必要であると考えられた

Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese Reviewed

N Ariyoshi, H Sekine, K Nakayama, K Saito, A Miyamoto, T Kamataki

PHARMACOGENETICS 14 ( 10 ) 701 - 705 2004.10

Effects of Continuous Ingestion of Green Tea or Grape Seed Extracts on the Pharmacokinetics of Midazolam Reviewed

NISHIKAWA Masataka, ARIYOSHI Noritaka, KOTANI Akira, ISHII Itsuko, NAKAMURA Hiroyoshi, NAKASA Hiromitsu, IDA Mayuri, NAKAMURA Hideo, KIMURA Nobuhito, KIMURA Maharu, HASEGAWA Atsushi, KUSU Fumiyo, OHMORI Shigeru, NAKAZAWA Kazuyoshi, KITADA Mitsukazu

Drug Metabolism and Pharmacokinetics 19 ( 4 ) 280 - 289 2004.8

Language：English Publisher：The Japanese Society for the Study of Xenobiotics

Limited systematic data on herb-drug interaction are available, despite many opportunities to concomitant use of herb with prescribed drugs. We investigated the effects of 15 herbal extracts in dietary supplements on CYP2C9, CYP2D6 and CYP3A4 activities in human liver microsomes. Strong inhibition of these CYP activities was found by the addition of green tea extracts (GTE) or grape seed extracts (GSE) in vitro. To examine the effects of these extracts on CYP3A activities in vivo, the pharmacokinetics of midazolam (MDZ) was analyzed in rats. Although single treatments with these extracts had negligible effects, 1 week of treatment with them resulted in a significant increase in the ke of intravenously administered MDZ, indicating the induction of CYP3A in the liver. In contrast, 1 week of treatment with GTE, but not GSE, caused a significant increase in the C_max and AUC_0-∞ of orally administered MDZ without change in the t_1/2, suggesting a reduction in CYP3A activity in the small intestines. These studies indicate that subchronic ingestion of GTE or GSE may alter the pharmacokinetics of MDZ, and the effects of GTE on CYP3A activity appear opposite between liver and small intestine, which could not be predicted from in vitro experiments.<br>

DOI： 10.2133/dmpk.19.280

Other Link： http://search.jamas.or.jp/link/ui/2006149345

The use of urine to clarify the genotype of a patient with toxic phenytoin concentrations who had undergone peripheral blood stem cell transplantation. Reviewed International journal

Noritaka Ariyoshi, Katsuhiro Sho-no, Miki Nishimura, Michihiro Ito, Hiroyoshi Nakamura, Takayoshi Asai, Yasushi Saitoh, Takashi Ishizaki, Mitsukazu Kitada

British journal of clinical pharmacology 58 ( 2 ) 225 - 6 2004.8

【健康食品・植物成分の薬物療法への影響】健康食品の薬物動態への影響

有吉範高

日本病院薬剤師会雑誌 40 ( 8 ) 955 - 957 2004.8

Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4 Reviewed

N Torimoto, Ishii, I, M Hata, H Nakamura, H Imada, N Ariyoshi, S Ohmori, T Igarashi, M Kitada

BIOCHEMISTRY 42 ( 51 ) 15068 - 15077 2003.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER CHEMICAL SOC

CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrate including endogenous steroids and some drugs that coexist at the active site. To clarify the mechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates, nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoretical calculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressed CYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkably increased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especially large, permitting access of two substrate molecules. The interactions between NVP and aldosterone and between CBZ and androstenedione were estimated by theoretical calculations assuming the substrate and steroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stably fixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting that NVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was also expected to interact with NVP via a pi/pi interaction between a benzene ring, in which the NVP hydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. From these results, interactions between the substrate and endogenous steroids in the active site may change the activity of CYP3A4.

DOI： 10.1021/bi034409n

病院薬剤師と薬局薬剤師の連携実習型調剤技術懇話会の参加者の評価

中村安孝, 仲佐啓詳, 長谷川敦, 松島徹, 木村真春, 柴田みづほ, 三浦剛, 稲野祥宗, 大塚知子, 明石利恵子, 丹野恵子, 有吉範高, 中澤一純, 中村均, 大森栄, 北田光一

薬学雑誌 123 ( 6 ) 463 - 468 2003.6

CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids Reviewed

H Nakamura, N Torimoto, Ishii, I, N Ariyoshi, H Nakasa, S Ohmori, M Kitada

DRUG METABOLISM AND DISPOSITION 31 ( 4 ) 432 - 438 2003.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Recently, we reported that several endogenous steroids affect CYP3A4-mediated drug metabolism, using human adult liver microsomes as an enzyme source. Especially, carbamazepine (CBZ) 10,11-epoxidation is activated by androstenedione (AND). In the present studies, we investigated the effects of endogenous steroids on the activity of CBZ 10,11-epoxidation by expressed CYP3A4 and CYP3A7. When expressed CYP3A4 was used as an enzyme source, the addition of AND to the reaction mixture also caused a drastic increase in the activity of CBZ 10,11-epoxidase, and resulted in a change in the kinetics from sigmoid to Michaelis-Menten type. On the other hand, expressed CYP3A7-mediated CBZ 10,11-epoxidation was activated by sulfate conjugate steroids, such as pregnenolone 3-sulfate, 17alpha-hydroxypregnenolone 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEA-S), whereas the unconjugated form corresponding to these three steroids did not activate the reaction. Especially, DHEA-S was found to be a potent activator of CBZ 10,11-epoxidation by expressed CYP3A7. The kinetic character of CBZ 10,11-epoxidation by CYP3A7 is Michaelis-Menten type regardless of the presence of DHEA-S. The presence of DHEA-S caused a decrease in K-m and increase in V-max for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16alpha-hydroxylation was not affected by the coexistence of CBZ. In conclusion, CYP3A4 and CYP3A7-mediated CBZ 10,11-epoxidations are activated by different types of endogenous steroids. This is the first report regarding CYP3A7 cooperativity.

DOI： 10.1124/dmd.31.4.432

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