JP5133064B2 - ウリジン2リン酸(udp)−グルクロン酸転移酵素2b(ugt2b)の抑制剤及び促進剤 - Google Patents
ウリジン2リン酸(udp)−グルクロン酸転移酵素2b(ugt2b)の抑制剤及び促進剤 Download PDFInfo
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- JP5133064B2 JP5133064B2 JP2007549784A JP2007549784A JP5133064B2 JP 5133064 B2 JP5133064 B2 JP 5133064B2 JP 2007549784 A JP2007549784 A JP 2007549784A JP 2007549784 A JP2007549784 A JP 2007549784A JP 5133064 B2 JP5133064 B2 JP 5133064B2
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- nalbuphine
- ugt2b
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- inhibitor
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Description
尚、UGTsには、又広範な基質特異性(substrate specificity)がある。UGTlA及びUGT2Bが代謝する化合物は同じではない、UGTlAは主としてエストロン(estrone)、2-ハイドロキシエストロン(2-hydroxyestrone)、4-ニトロフェノール(4-nitrophenol)、1-ナフトール(1-naphthol)などのフェノリック化合物(phenolic compounds)などを代謝し、そしてビリルビン(bilirubin)がこの代謝に関与する、一方、UGT2B族は、アンドロステロン(androsterone)、リノール酸(linoleic acid)などステロイド化合物(steroid compounds)を代謝し、そして胆汁酸(bile acids)がこの代謝に関与する。
従って、肝臓疾患(liver diseases)を患う個体中のUGTs活性に欠陥がある場合、グルクロン酸抱合の作用に影響し、肝臓の薬物代謝に対するクリアランス比(clearance rate)を引き下げ、個体の中毒反応を高め、ガンにかかる確率が増大する。
胃腸を経由して吸収される大部分の薬物は全身を循環する前に、先ず肝門脈を通って肝臓へ循環・到達し、肝細胞の代謝過程を経る、此れが初回通過効果(first-pass effect)である。腸道及び肝臓中に豊富に存在するUGTsは、薬物が吸収された後初回通過効果を生じる主要酵素の一つであることが実証されている。初回通過効果を生じた薬物は、低い且つ変異性の生体利用性を有する。
又或る文献には、ジアゼパム(diazepam)及びフルニトラゼパム(flunitrazepam, FM2)がUGT2Bの活性を強烈に抑制できると報告されている(Grancharov et al., 2001, harmacol Ther.,89(2):171-86)。
当業者なら、薬物の生体利用性の増加に使用できるUGT抑制剤には、少なくとも下記3種類の特性を備えていなければならないことを認知しているはずである:(1)UGTsを抑制するほか、薬理効果(pharmacological effect)がないか又は最低であること;(2)抑制作用は可逆性でなければならない、言い換えれば、一旦この抑制剤が体外に排出又は代謝されると、UGTsの正常な代謝機能を回復できること;及び(3)その抑制剤の効力は最低分量によっても腸道や肝臓のUGTs活性を抑制するに足るものであること。
近年来、薬学界では既に、グレープフルーツのジュース又はその他天然物の中のある種の組成分がある種の薬理活性(pharmacological activities)を制限することが次第にわかって来ている、例えば、ナリンジン(naringin)、ナリンゲニン(naringenin)及びヘスペリジン(hesperidine)等のフラボノイド類(flavonoids)がそうである。
現在、ナルブフィンは主としてUGT2B7を経由して代謝されることが文献で証明されている。(Radominska-Pandya et al., 1999)。
そこで、本案発明は又、
(a) 薬学的有効量の前述UGT2B抑制剤、及び
(b) 薬学上許容されるキャリヤー剤、
を含む薬学的組成物を提供する。
(a)薬学的有効量の前述UGT2B促進剤、及び
(b)薬学上許容されるキャリヤー剤、
を含む薬学的組成物を提供する。
(1−1)材料及び方法:
1. UGT2B抑制剤の調合
本案発明の下記実験では、合計27種の漢方薬の副薬及び10種類の賦型剤を採用してUGT2B抑制剤とした、これらの漢方薬の副薬は、すべて商品化された純質の化合物であり、それぞれSigma Chemical Co.、acalai Tesque (Kyoto, Japan)及びINDOFINE Chemical Co., Inc. (Somerville, New Jersey)から購入した。これらの漢方薬の副薬の種類・名称・生薬の出所及び化学式は下記表1に示す通りである。これらのUGT2B抑制剤をアルコールでそれぞれ1、10、100μMの濃度に調合して、実験をおこなった。
尚、賦型剤部分はすべて商品化された純質化合物で、それぞれポリエチレングリコールPEG(Polyethylene glycol)400、ポリエチレングリコール2000(PEG 2000)、ポリエチレングリコール4000(PEG 4000)、ツウィーン20(Tween20)、ツウィーン60(Tween 60)、ツウィーン80(Tween 80)、BRIJ 58、BRIJ 76、プルロニックF68(Pluronic F68)、プルロニックF127(Pluronic F127)である。これらの賦型剤を水でそれぞれ0.5%、5%、50%(重量・百分比、w/v)の濃度に調製して以後の実験に備えた。[注:BRIJはICI Americas, Inc.の登録商標名;PluronicはBASF Corporationの登録商標名である]
本実験では、体重範囲が300-400グラムの雄ラット(Sprague-Dawley rat)をモデル動物とした。本実験は、下記のステップで微粒体を調製した:
i. 禁食12-16時間のラットを敲いて失神させ、肝臓を取り出し、肝臓表面の水分を吸い取って乾かし、重量を測る。
ii. 次に3倍体積の冷蔵0.3Mショ糖溶液を加え、且つ均質機で肝臓をすり砕く。
iii. 4℃で、すり砕いた後の肝均質液を9000 × gの回転スピードで遠心分離(KS-800, Kubota,日本)を行い、10分間経過後、上清液を取り出す、
iv. 4℃で、取り出した上清液を105,000×g の回転スピードで超高速遠心分離(L8-60M, Beckman, 米国)を行い、60分経過後、
v. 上清液を取り除き、等体積の0.3Mショ糖溶液を加え、再び均質機ですり砕く。すり砕いた後の肝均質液が微粒体(microsome)で、-70℃の冷蔵庫に保存する。
[注:BRIJ35 SOLUTION 30% W/V,BRIJ is a registered trademark of ICI Americas, Inc.]
この実験では、下記ステップでタンパク質含有量の測定を行った:
I. 0.1 mlの微粒体を0.85 % NaClで5ml (50倍体積比で希釈)まで希釈し、その中から0.2 mlを取り出し、且つキャップ付き試験管の中に置く、(3回繰り返す);別途、微粒体の代わりに0.2 ml NaClを使用して本実験の対照組とする。
II. それぞれ試験管毎に2.2 ml Biuretの試薬(SIGMA, 690-A)を加え、均一に混合した後、室温で10分間放置する。
III. それぞれ試験管毎に0.1 ml folinの試薬(SIGMA, 690-A)を加え、直ちに均一混合した後、室温で30分間放置し、30分間以内に、550 nm波長における吸光密度を測定し、タンパク質(牛血清蛋白Bovine albumin)濃度-吸光値の標準曲線を利用して、前記測定された微粒体中のタンパク質含有量を計算する。
1. (A)溶液:17μlの1M Tris-HCl緩衝溶液、17μlの50mM MgCl2水溶液、40μlの微粒體と10μlの150mM UDPGA水溶液、
(B)溶液:体積比1:1の方式で20mMのナルブフィン水溶液及び測定すべき抑制剤を混合する、
2. (A)溶液と17μlの(B)溶液の混合液を十分混合した後、37℃で湯煎し、振動速度125 rpmで60分間反応させる、
3. 時間が終了したら、1ml ACNの中に入れて反応を中止する。
4. 4℃で、130,000 ×gの回転スピードで5分間遠心分離させる、
5. 上清液150μlを取り出し、且つ高速液体クロマトグラフ装置(HPLC)に入れてナルブフィンの濃度を分析する。
(1) 高速液体クロマトグラフ装置の分析条件
移動相 (mobile phase) は、15酢酸ナトリウム緩衝液 (5ミリモール/リットル,pH 3) 及び85%ACNによって組成され、使用した流速は毎分1.0ミリリットル,蛍光計測器(RF-551,Shimadzu, Kyoto, 日本)の励起光波長は210 nm、放射光波長は345 nm;紫外光計測器(SPD-10A, Shimadzu, Kyoto, 日本)で使用した波長は210 nmである。
(2) 標準溶液の調製
ナルブフィンを0.5、1、2.5、5、10、15、18、20 mMの濃度に調製する。標準溶液は水で調製し、抑制剤を含むものはアルコールで希釈する。
各濃度の標準溶液を上述「4. UGT2B酵素活性の体外抑制を測定する方法」のステップで行う、但し(A)溶液中の「150mM UDPGA水溶液」は「脱イオン水」に替える。
上述実験結果の漢方薬の副薬に関する部分を表2に示す。肝微粒体のナルブフィン代謝に対するカピラリシンの抑制効果が最もよく、111.077 (±21.807) % の抑制率が得られた;その他の漢方薬の副薬、イソラムネチン、β-naphthoflavone、α-naphthoflavone、へスぺリチン、ピノレジノール、(+)-リモネン、β-ミルセン、スウェルチアマリン及びエリオジクチオールなども、少なくとも約30%の抑制率が得られた。
(2−1)
本実施例は、実施例1に述べたのと同じステップによって行った、但し、下記表5に記した40種の漢方薬の副薬をUGT2B促進剤として採用した、これらの漢方薬の副薬はすべて商品化された純質の化合物であり、それぞれSigma Chemical Co.、Nacalai Tesque (Kyoto, Japan)及びINDOFINE Chemical Co., Inc. (Somerville, New Jersey)から購入した。これらの漢方薬の副薬の種類、名称、生薬の出所及び化学式は下記表5に示す通りである。
上述実験結果を表6に示す。 肝微粒体のナルブフィン代謝に対するノルジヒドログアヤレチック酸の促進効果が最もよく、-188.09(±16.566)%の抑制率が得られた、その他の漢方薬の副薬、wogonin, trans-cinnamic acid, baicalein, quercetin, daidzein, oleanolic acid, homoorientin, hesperetin, narigin, neohesperidin, (+)-epicatechin, hesperidin, liquiritin, eriodictyol,なども、少なくとも約30%の促進率が得られた。
(3−1)材料及び方法:
1. 実験動物
動物の出所は実験用の雄ラットSprague-Dawley品種で、体重が500-600gの間にある健康なラットを主体とし、台湾実験国家科学委員会動物センター(National Laboratory Animal Breeding and Research Center, Taiwan)から購入。購入後、動物に一週間の適応期間を与え、固定温度(25 ± 1oC)、湿度及び光周期(毎日12時間光照明)下において飼育した。実験前約12-16時間禁食。実験方法は口服方式で薬物の吸収を評価した。
ナルブフィンの標準溶液は水で調製し、抑制剤はアルコールで調整した。
i. (I.P.)3~5mg/100g体重のペントバルビタール(pentobarbital)を腹膜内に注射し、約20~30分間経過した後、ラットは深度の麻酔状態を呈した;
ii. PE-50挿管を頚部中心線右よりの頚部静脈(external jugular vein)に導入し、血液サンプルを抽出した;
iii. 実験組のラット6匹に口服方式でUGT 2B抑制剤カピラリシン (4mg/Kg体重)及びナルブフィン(100mg/Kg体重)の分量を与え、別のラット6匹には、ナルブフィン(100mg/Kg体重)の分量のみを与えて、対照組とした。それぞれ投薬後の0.25、0.5、0.75、1、1.5、2、3、4、6、8、12、24時間に、PE-50挿管で0.3 mLの血液サンプルを抽出し、10000 rpmで遠心分離した後、0.1 mLの血漿で血漿中のナルブフィン濃度を分析した。
(1) サンプルの調製
0.1 mLの血漿を10 mLの試験管に注入した後、速やかに氷水浴の中に移し、更に50 μLの内部標準(intermal standard,布皮諾芬 5 μg/mL)及び0.5 mLの炭酸ナトリウム緩衝液(0.5モール/リットル,pH=9.25)を均一に混合して、更に4 mLのノルマルヘキサン (n-Hexane)及びイソアミルアルコール(isoamyl alcohol)の混合液(体積/体積比=9:1)で血漿中の薬物を抽出し、20分間振動混合し、4℃で、1,080×gの回転速度にて15分間遠心分離を行い、水層が氷結するまで、-80℃より低い冷凍庫の中に入れ、有機層を清潔な試験管の中に移しいれ、真空遠心分離法によって有機溶剤を揮発させ、且つ100μLのACN溶出して乾燥済みの薬物を、オートピペット(autopipette)で50μLの溶出物を高速液体クロマトグラフ・システムの中に入れ、その濃度を分析した。
移動相は15%酢酸ナトリウム緩衝液 (5ミリモール/リットル,pH=3.75) 及び85%ACNによって組成され、使用した流速は毎分1.3 Mlで、電気化学計測器(electrical chemical detector, ECD (electrochemical detector), Coulochem II, ESA)によって計測した(E1=200mv、E2=400mv、E=500mv)。
ACNに溶解したナルブフィン薬物を血漿によって5、10、20、50、100、200、500、1000、2000、3000 ng/mL の濃度に調整した。
各濃度の標準溶液を上述「(1)サンプルの調製」のステップで行い、HPLCで分析した後、クロマトグラムのナルブフィン薬物の波峰高さの値及びその相対濃度をプロットすると、校正曲線が得られると共に、標準偏差(standard deviation, SD)・変異係数(%CV)及び誤差(%error)によって精密性及び正確性を検証することが出来る。
先ず、表7を参照して、薬物動力学の角度からナルブフィンの血液中の変化を検討した。対照組と実験組両者のTmax、AUC、Cmax、CL/F、V/Fには明らかな差異性が見られる、表7から、SDラットに口服式で100 mg/Kgのナルブフィン及び4mg/Kgのカピラリシンを投薬したあと、血液中最高濃度に達する時間(Tmax)は25±5minで、血液中最高濃度は(Cmax)は2582.3±906.6 ng/mlであることが分かる。一方、100 mg/Kgのナルブフィンのみを投与した場合、血液中最高濃度に達する時間(Tmax)は97±36 minで、血液中最高濃度は(Cmax)は79.31±18 ng/mlであった。
(4−1)材料及び方法:
本実施例は、実施例3の中で述べた「材料及び方法」と同じ方法で行った、但し、「3. 実験方法」のステップで、更に余分に頚動脈に対する挿管のステップを増やして、静脈から投薬し、動脈から血液サンプルを取った。このステップは、前記方法中のステップiiに同じであるが、注意すべきことは、動脈クリップで用心深く心臓に近い方の血管を挟み付けて大出血を避けなければならないことで、且つ血管に差し込む距離は約2.5 cmでよい。
対照組と実験組のラットにそれぞれ投薬した後の15、20、30、45、60、90、120、180分間に、PE-50挿管によって0.3 mLの血液サンプルを抽出し、血漿中のナルブフィン濃度を分析した。
先ず、表8を参照して、薬物動力学の角度からナルブフィンの血液中の変化を検討した。対照組と実験組両者のAUC、Cmax、CL/F、V/Fには明らかな差異性があり、表8から分かることは、SDラットに静脈注射方式で100 mg/Kgのナルブフィン及び4mgのカピラリシンを投与した後、血液中最高濃度(Cmax)は365±119 ng/mlであることが分かる。一方、100 mg/Kgのナルブフィンのみを投与した場合、血液中最高濃度(Cmax)は154±30 ng/mlであった。
上述結果は、カピラリシンの静脈注射投与がUGT2Bに対して抑制作用があるため、ナルブフィンの濃度を対照組の32.68倍に増加させ、絶対生体利用性が2.7 ±0.4% になった。 SD ラットの口服薬にカピラリシンを添加しない場合、絶対生体利用性は12.759 ±4.64%に達し、 SD ラットのナルブフィン口服にカピラリシンを添加した場合、絶対生体利用性は127.85 ±36.41%に引き上げられた。
又、図2は、SDラットにナルブフィンを静脈注射した後、異なる時間下でのカピラリシンの血液中ナルブフィン濃度に対する影響を表す。図2を参照して、対照組及び実験組両者にそれぞれ投薬した後、時間の増長に伴い、両者間ナルブフィン濃度濃度の差異が次第に増加し、180分の時に、実験組の血漿中ナルブフィン濃度濃度は明らかに対照組より2.37倍高くなった。
(5−1)材料及び方法:
本実施例は実施例3及び4の中で述べた「材料及び方法」と同じ方法で行った。
ナルブフィンをそれぞれ口服及び静脈注射した両組の対照組とナルブフィン及びカピラリシンを口服した実験組のラットに投薬した後、PE-50挿管によって0.3 Mlの血液サンプルを抽出し、血漿中のナルブフィン濃度を分析した。
図3は、ナルブフィンを口服及び静脈注射した両組の対照組と、ナルブフィン及びカピラリシンを口服した実験組において、SDラットの異なる時間下における血液中ナルブフィン濃度の変化を表す。
口服吸収は、主として下記三つの要素、腸胃道吸収・初回通過効果及びその他の部分の代謝、の影響を受け、一方、静脈注射は、主として初回通過効果以外の代謝の影響を受ける、従って、図3から、抑制剤を添加した口服吸収と薬物のみを静脈注射した対照組を比較すると、抑制剤が存在する場合は明らかに口服吸収の情況を改善出来、絶対生体利用性が5 %から108 %に向上し、且つ両組のAUC値は非常に近似していることが分かる、此れは、抑制剤の添加がナルブフィンの口服吸収効果を促進することを意味する。[ 注:表5と表6のデータを比較すると、表5のナルブフィン及びカピラリシン口服のAUC(総量)値は244071 ± 69510であり、一方静脈注射した対照組のAUC(総量)値は7135 ± 1218で、上述した内容と一致しないように見えるが、これはナルブフィンを口服した時の分量は100 mg / Kgで、静脈注射した時の分量は1 mg / Kgであったためである。]
Claims (5)
- 薬学的有効量のモルヒネ類鎮痛剤(morphine-like analgesic agents) と、
薬学的有効量のグルクロン酸転移酵素2Bの抑制剤(UGT2B抑制剤)と、
薬学上許容されるキャリヤー剤と、を含む、
薬学的組成物であって、
前記UGT2B抑制剤は、ソルトフリーまたは薬学上で許容される塩類形式で、アピゲニン(apigenin)、イソラムネチン(isorhamnetin)、ヘスペレチン(hesperetin)、カピラリシン(capillarisin)、α-ナフトフラボン(α-naphthoflavone)、β-ナフトフラボン(β-naphthoflavone)からなるグループより選択されることを特徴とする、薬学的組成物。 - 前記モルヒネ類鎮痛剤は、(-)-モルヒネ((-)-morphine)、ナロキソン(naloxone)、ナロルフィン(nalorphine)、オキシモルホン(oxymorphone)、ハイドロモルフォン(hydromorphone)、ジハイドロモルフォン(dihydromorphine)、コデイン(codeine)、ナルトレキソン(naltrexone)、ナルトリンドール(naltrindole)、ナルブフィン(nalbuphine) 、ブプレノルフィン(buprenorphine)、からなるグループより選択されることを特徴とする、請求項1に記載の薬学的組成物。
- 前記モルヒネ類鎮痛剤はナルブフィンであることを特徴とする、請求項2に記載の薬学的組成物。
- 注射剤タイプの形式で作られたことを特徴とする請求項1に記載の薬学的組成物。
- 口服剤タイプの形式で作られたことを特徴とする請求項1に記載の薬学的組成物。
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