JP4940438B2 - 疎水性薬物検出法 - Google Patents
疎水性薬物検出法 Download PDFInfo
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- JP4940438B2 JP4940438B2 JP2010538187A JP2010538187A JP4940438B2 JP 4940438 B2 JP4940438 B2 JP 4940438B2 JP 2010538187 A JP2010538187 A JP 2010538187A JP 2010538187 A JP2010538187 A JP 2010538187A JP 4940438 B2 JP4940438 B2 JP 4940438B2
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- hydrophobic
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9493—Immunosupressants
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Description
本発明の一つの実施態様は、疎水性薬物の生物学的利用能をその疎水性薬物の代謝産物よりも選択的に高める方法である。組み合わせが媒体中に提供される。組み合わせは、(i)試料、(ii)疎水性薬物及びその代謝産物を内在性結合成分から遊離させるための遊離剤、及び(iii)媒体中、代謝産物の生物学的利用能に対する疎水性薬物の生物学的利用能の向上を提供する選択的可溶化剤を含む。選択的可溶化剤は、水混和性の不揮発性有機溶媒を含み、媒体中、疎水性薬物の生物学的利用能を代謝産物の生物学的利用能よりも高めるのに十分な濃度で媒体中に存在する。媒体は、疎水性薬物の生物学的利用能を代謝産物の生物学的利用能よりも高めるための条件下で、インキュベート(培養)される。
概要説明
本発明者らは、薬物及び代謝産物のタンパク質結合性を低下させることにより、そして、アッセイ混合物中の疎水性薬物の溶解性を、疎水性薬物そのものよりも親水性であると本発明者らが認識した疎水性薬物の代謝産物の溶解性に対して高めることにより、薬物代謝産物の交差反応性を低下させうることを認識した。薬物代謝産物のより高い親水性は、薬物代謝から肝臓を介して脱メチル化及びヒドロキシル化によって生じる余分なヒドロキシル基のせいであると思われる。疎水性相互作用は、水性血液中の薬物−タンパク質結合にとって重要かつ一般的な機構である。本発明者らは、親水性代謝産物が結合タンパク質に対してより低い親和力を有し、水性血液及びアッセイ混合物中でより自由に拡散する傾向を示すことを観測した。その理由のため、代謝産物分子のより大きな部分は自由な非タンパク質結合状態であり、水性アッセイ混合物中、親薬物よりもアッセイ抗体によりアクセス可能である。薬物代謝産物がアッセイ抗体に対して親薬物と同じ結合親和力を有すると仮定すると、代謝産物は、そのより高いアクセス可能性のおかげで、親薬物よりも抗体とでより多くの免疫複合体を形成する。上記認識は、代謝産物交差反応性は抗体結合親和力の関数でしかないという一般的信念に反するものである。本発明者らは、そのようなアッセイにおける代謝産物の交差反応性が、その抗体結合親和力に依存するだけでなく、内在性結合タンパク質に対するその結合親和力にも依存すると判定した。
溶血剤とは、赤血球の膜の結着性を崩壊させて、それにより、細胞の内容物を放出させる化合物の配合物又は混合物である。数多くの溶血剤が当該技術で公知である。溶血剤としては、たとえば、非イオン界面活性剤、アニオン界面活性剤、両性界面活性剤、低イオン強度水溶液(低張溶液)、細菌剤、補体依存性溶菌を生じさせる抗生物質などがある。溶血剤として使用することができる非イオン界面活性剤としては、合成界面活性剤及び天然界面活性剤の両方がある。合成界面活性剤の例は、TRITON(商標)X-100、TRITON(商標)N-101、TRITON(商標)X-114、TRITON(商標)X-405、TRITON(商標)SP-135、TWEEN(登録商標)20(ポリオキシエチレン(20)ソルビタンモノラウレート)、TWEEN(登録商標)80(ポリオキシエチレン(20)ソルビタンモノオレエート)、DOWFAX(登録商標)、ZONYL(登録商標)、ペンタエリトリチルパルミテート、ADOGEN(登録商標)464、ALKANOL(登録商標)6112界面活性剤、アリルアルコール1,2−ブトキシレート−ブロック−エトキシレートHLB6、BRIJ(登録商標)、エチレンジアミンテトラキス(エトキシレート−ブロック−プロポキシレート)テトロール、IGEPAL(登録商標)、MERPOL(登録商標)、ポリ(エチレングリコール)、2−[エチル[(ヘプタデカフルオロオクチル)スルホニル]アミノ]エチルエーテル、ポリエチレン−ブロック−ポリ(エチレングリコール)、ポリオキシエチレンソルビタンテトラオレエート、ポリオキシエチレンソルビトールヘキサオレエート、TERGITOL(登録商標)NP-9、GAFAC(登録商標)(RHODAFAC(登録商標)、アルキルポリエチレングリコールリン酸エステル、たとえばアルファ−ドデシル−オメガ−ヒドロキシポリ(オキシ−1,2−エタンジイル)ホスフェート)及びEP110(登録商標)などを含む。溶血剤として使用することができる天然界面活性剤としては、たとえば、サポニン、ナトリウム又はカリウム中和された脂肪酸、中和リン脂質、ジアシルグリセロール、中和ホスファチジルセリン、ホスファチデート、中和ホスファチジルエタノールアミン、ホスファチジルコリン、ホスファチジルイノシトール、ホスファチジルコリン、胆汁酸塩、非エステル化コレステロール、中和スフィンゴシン、セラミドなどがある。一つ以上の合成界面活性剤又は一つ以上の天然界面活性剤の組み合わせ及び合成界面活性剤と天然界面活性剤との組み合わせを使用することもできる。
遊離剤は、疎水性薬物を内在性結合成分から移動させる。遊離剤は、疎水性薬物の代謝産物を内在性結合成分から移動させることができ、多くの場合、そのように移動させる。多くの実施態様において、遊離剤は、内在性結合タンパク質に対して高い結合親和力を有し、そのため、疎水性薬物及びその代謝産物を内在性結合タンパク質から容易に移動させる。加えて、遊離剤は、アッセイで使用される薬物のための抗体には有意な程度には結合しない。「有意な程度には結合しない」とは、結合の程度が、薬物の正確なアッセイを実施するのに十分な低さであるべきであることをいう。遊離剤は、アッセイ抗体に有意に結合することなく所望の移動の結果を達成する任意の成分、単一の化合物又は化合物の混合物であることができる。多くの実施態様において、遊離剤は、疎水性薬物及びその代謝産物を内在性結合物質から移動させて、疎水性薬物及び代謝産物の両方を疎水性薬物のための抗体に実質的に等しくアクセス可能にする。「実質的に等しくアクセス可能」とは、抗体への結合に利用可能な疎水性薬物の量が、抗体への結合に利用可能な疎水性薬物の代謝産物の全量から有意な程度には異ならないことをいう。疎水性薬物のための抗体への結合に利用可能な代謝産物の量は、たとえば、疎水性薬物のための抗体に対する具体的な代謝産物の結合親和力のような考慮事項に依存する。上記の見込みは、薬物代謝産物が、疎水性薬物のための抗体に対し、疎水性薬物そのものとほぼ同じ結合親和力を有するという仮定に基づく。そうでなければ、上記の見込みは、疎水性薬物代謝産物の実際の結合親和力に基づいて調節されるべきである。
選択的可溶化剤は、媒体中、疎水性薬物の生物学的利用能と代謝産物の生物学的利用能との均等化を促進する。選択的可溶化剤の性質は、遊離剤によって内在性結合成分から遊離される薬物及び/又は薬物代謝産物を溶解させるための準疎水性環境を提供するような性質である。選択的可溶化剤を使用することにより、薬物及び代謝産物はアッセイ抗体に同様にアクセス可能になり、そうでなければ、親薬物に比較して低いタンパク質結合及び高純度の水溶液中での高い可溶性のせいでより高くなるであろう代謝産物公差反応性の低下が得られる。本明細書の実施態様の選択的可溶化剤の存在は、遊離された薬物及び代謝産物の両方が前処理媒体及び/又はアッセイ媒体中に実質的に等しく溶解することを保証する。いくつかの実施態様において、選択的可溶化剤は、アッセイで使用される疎水性抗体の生物学的利用能を高める。
試料、溶血剤(使用する場合)、遊離剤及び選択的可溶化剤を、上述したように通常は水性媒体であり、本明細書では前処理媒体と呼ばれる媒体中で組合わせる。上記のすべては、媒体中で同時に組合わせることもできるし、上記試薬の一つ以上を上述したような濃度で順次に加えることもできる。媒体はまた、当該技術で公知であるような一つ以上の保存剤、たとえばアジ化ナトリウム、硫酸ネオマイシン、PROCLIN(登録商標)300、ストレプトマイシンなどを含むこともできる。媒体のpHは、通常は約4〜約11の範囲、より通常は約5〜約10の範囲、好ましくは約6.5〜約9.5の範囲である。
上記インキュベーション期間ののち、試料中の疎水性薬物の存在及び/又は量を測定するための試薬が媒体に加えられる。試薬の性質は、実施されるアッセイの具体的なタイプに依存する。一般に、アッセイは、疎水性分析対象の存在及び/又は量を決定又は測定するための方法である。以下、様々なアッセイを非限定的な例として説明する。
本開示の方法による次のステップで、媒体を、疎水性薬物及び疎水性薬物のための抗体を含む複合体の存在に関して試験する。複合体の存在及び/又は量は試料中の疎水性薬物の存在及び/又は量を示す。
以下の実施例は、本発明の具体的な実施態様を例として記載するが、本発明を説明することを意図したものであり、その範囲を限定することを意図したものではない。
本発明の一つの実施態様は、疎水性薬物を検出するためのアッセイ法を実施するために、疎水性薬物を含有することが疑われる試料を前処理する方法である。組み合わせが媒体中に提供される。組み合わせは、(i)試料、(ii)疎水性薬物及びその代謝産物を内在性結合成分から遊離させるための遊離剤、及び(iii)媒体中に疎水性薬物及びその代謝産物の実質的に等しい溶解性を提供する選択的可溶化剤を含む。選択的可溶化剤は、水混和性の不揮発性有機溶媒を含み、媒体中に疎水性薬物及びその代謝産物の実質的に等しい溶解性を提供するのに十分な濃度で媒体中に存在する。媒体は、免疫抑制薬及びその代謝産物を内在性結合成分から遊離させるための条件下で、インキュベートされる。
材料
断りない限り、すべての薬品は、Sigma-Aldrich Company(St. Louis MO)から購入された。シロリムス粉末及びその代謝産物は、27,39−O−ジデスメチル(又は32,41−O−ジデスメチル)シロリムスを除き、すべてWyeth Pharmaceuticalsから得られた。27,39−O−ジデスメチル(又は32,41−O−ジデスメチル)シロリムスは、Dr. Uwe(Christains laboratory at Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado)から頂いた。
非手作業的前処理を使用する、異なる程度の代謝産物交差反応性を有する疎水性薬物の自動化イムノアッセイ
FK−506カルバメート(FKE)を用いない前処理溶液の調製
この前処理溶液は、pH6.5で6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、0.09%PLURONIC(登録商標)25R2、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有するように調製した。この溶液には有機溶媒を加えなかった。
この前処理溶液は、pH6.5で3.75μg/mL FK−506カルバメート化合物(又はタクロリムスエステル)、6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、0.09%PLURONIC(登録商標)25R2、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有するように調製した。この溶液には有機溶媒を加えなかった。最終反応混合物中のFKE濃度は0.86μg/mLであった。
この前処理溶液は、15μg/mL FK−506カルバメート化合物(又はタクロリムスエステル)、6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、0.09%PLURONIC(登録商標)25R2、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有するように調製した(pH6.5)。この溶液には有機溶媒を加えなかった。最終反応混合物中のFKE濃度は3.4μg/mLであった。
この前処理溶液は、緩衝剤にDMSOを最終濃度10%(v/v)まで加えることによって調製され、この緩衝剤は、pH6.5で、6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、15μg/mL FK−506カルバメート化合物(又はタクロリムスエステル)、0.09%PLURONIC(登録商標)25R2、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有した。最終反応混合物中のDMSOの濃度は約2.3%であった。
この前処理溶液は、緩衝剤にDMSOを最終濃度15%(v/v)まで加えることによって調製され、この緩衝剤は、pH6.5で、6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、15μg/mL FK−506カルバメート化合物(又はタクロリムスエステル)、0.09%PLURONIC(登録商標)25R2、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有した。最終反応混合物中のDMSOの濃度は約3.4%であった。
この前処理ベース溶液は、緩衝剤に1−メトキシ−2−プロパノール(MP)を最終濃度10%(v/v)まで加えることによって調製され、この緩衝剤は、pH6.5で、6.8mg/mL PIPES(商標)1.5ナトリウム塩、0.3mg/mL EDTA二ナトリウム、1.0mg/mLサポニン、15μg/mL FK−506カルバメート化合物(又はタクロリムスエステル)、0.2%Proclin 300、0.024mg/mL硫酸ネオマイシン及び0.99mg/mL NaN3を含有した。最終ACMIA反応混合物中のMPの濃度は約2.3%であった。
標準的ヘテロ二官能性SMCC(スクシンイミジルトランス−4−(N−マレイミジルメチル)シクロヘキサン−1−カルボキシレート)リンカを使用して、公知の技術にしたがってモノクロナール抗シロリムス抗体(Wyeth Pharmaceuticals, Cambridge MA)をβ−ガラクトシダーゼにコンジュゲートした。抗体コンジュゲート溶液は、pH6.5で、約7.5μg/mL抗シロリムス抗体−β−ガラクトシダーゼコンジュゲート、30mg/mLプロテアーゼフリーウシ血清アルブミン、0.126mg/mL MgCl2、0.03mL/mLエチレングリコール、35.14mg/mL PIPES1.5ナトリウム塩、50mg/mL NaCl及びβ−ガラクトシダーゼ突然変異タンパク質(不活性化β−ガラクトシダーゼ)を含有した。
N−ヒドロキシスクシンイミド(NHS)エステル及び1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(EDAC)の化学作用を使用してシロリムス−C26−又は−C32−CMOコンジュゲートをDA10−デキサル−二酸化クロム粒子にコンジュゲートすることにより、シロリムスクロム粒子(イムノアッセイ固相)を調製した。たとえば、関連する開示内容が参照によって本明細書に組み込まれる米国特許第6,231,982号を参照すること。そして、シロリムスクロム粒子をシロリムスクロム粒子錠剤に成形する。各シロリムス錠剤は、2mgシロリムスクロム粒子スラリー、30.4mgトレハロース二水和物及び3.6mg CARBOWAX(登録商標)100μmを含有する。
シロリムスのためのACMIAアッセイの原理及び手順は以下のとおりであった。DIMENSION(登録商標)RxLアナライザ上、選択的可溶化剤として有機溶媒を含有し、FKEを含む、又は含まない前処理試薬を反応容器に加えた。次に、シロリムス又はその代謝産物を含有する全血18μLを加えた。全血は、まず血液を超音波試料プローブと混合することにより、標準カップから採取した。全血試料と前処理溶液との混合が、タクロリムスカルバメート分子が存在するときの全血の溶血及びタンパク質結合シロリムス分子の結合部位からの移動を保証した。次に、抗シロリムス抗体−β−ガラクトシダーゼコンジュゲート(50μL)を加え、試料中のシロリムスと反応させた。固定化されたシロリムス−CMO−DA10−デキサルを有するクロム粒子(50μL)を加え、非結合コンジュゲートに結合させた。クロム粒子から溶液を分離するために上記反応混合物に磁場を印加すると、シロリムス結合抗シロリムス抗体−β−ガラクトシダーゼコンジュゲートは、クロム粒子には結合せず、上澄み中に残留した。上澄みを反応容器から測光キュベットに移し、クロロフェノールレッド−β−D−ガラクトピラノシド(CPRG)の存在におけるコンジュゲートの酵素速度を計測することにより、シロリムス結合コンジュゲートを検出した。速度は、577及び700nmで二色的に計測した。
10もしくは15%のDMSO又は10%のMPをFKEとともに使用して、全血試料中のシロリムス及びその代謝産物濃度を計測するためにDIMENSION(登録商標)RxLアナライザ上で実施されるACMIAアッセイのための別々の前処理溶液(上記で詳述したとおり)を製造した。上述の有機溶媒及びFKEなしのもう一つの前処理溶液をアッセイのための対照(「対照」)として製造した。前述の有機溶媒を添加された前処理溶液及び添加されていない前処理溶液を使用して、DIMENSION(登録商標)臨床化学アナライザ上でのシロリムスACMIAアッセイのための試薬カートリッジを調製した。上述の溶媒及びFKEを使用しなかった場合、すべての代謝産物は全血試料中で高い回収率を示した。以下の表には、シロリムス代謝産物の回収率を親薬物シロリムスの回収率に対する割合として報告する。
Claims (9)
- 疎水性薬物の生物学的利用能を前記疎水性薬物の代謝産物の生物学的利用能よりも選択的に高める方法であって、
(a)媒体中に、
(i)疎水性薬物を含有することが疑われる試料、
(ii)前記疎水性薬物及び前記代謝産物を内在性結合成分から遊離させるための遊離剤、及び
(iii)前記疎水性薬物のための選択的可溶化剤であって、前記選択的可溶化剤が水混和性の不揮発性有機溶媒を含み、前記媒体中の前記選択的可溶化剤の濃度が、前記媒体中、前記疎水性薬物の生物学的利用能を前記代謝産物の生物学的利用能よりも高めるのに十分である選択的可溶化剤
を組み合わせて提供すること、ならびに
(b)前記媒体を、前記媒体中、前記疎水性薬物の生物学的利用能を前記代謝産物の生物学的利用能よりも高めるための条件下で、インキュベートすること
を含む方法。 - 前記媒体中の前記組み合わせが、溶血剤をさらに含み、ステップ(b)において、前記試料中の細胞を溶血させるための、及び、前記媒体中、前記疎水性薬物の生物学的利用能を前記代謝産物の生物学的利用能よりも高めるための条件下で、前記媒体をインキュベートし、前記方法がさらに、ステップ(b)のあとに、
(c)前記試料中の前記疎水性薬物の存在及び/又は量を測定するための、前記疎水性薬物に特異的に結合する少なくとも一つの抗体を含む試薬を前記媒体に加えること、ならびに
(d)前記疎水性薬物及び前記疎水性薬物に特異的に結合する抗体を含む複合体の存在に関して前記媒体を試験し、前記複合体の存在及び/又は量が前記試料中の前記疎水性薬物の存在及び/又は量を示すこと
をさらに含む、請求項1記載の方法。 - ステップ(c)における前記試薬が前記疎水性薬物の類似体をさらに含み、少なくとも前記疎水性薬物のための前記抗体又は前記類似体が標識を含む、請求項2記載の方法。
- ステップ(c)において、第二の抗体を前記媒体に加え、前記第二の抗体が、前記疎水性薬物と前記疎水性薬物に特異的に結合する前記抗体との複合体に結合する、請求項2記載の方法。
- 前記疎水性薬物のための前記抗体及び前記第二の抗体の少なくとも一つが標識を含む、請求項4記載の方法。
- 前記疎水性薬物が免疫抑制薬である、請求項1記載の方法。
- 前記選択的可溶化剤が、2〜3個のヒドロキシ基を含むC2〜C6ポリオール、C2〜C6スルホキシド、C2〜C6スルホン又はC2〜C6アミド、ポリオールのC2〜C6モノ、ジ及びトリエーテル又はポリオールのC2〜C6モノ、ジ及びトリエステルである、請求項1記載の方法。
- 前記選択的可溶化剤が、エチレングリコール、グリセロール、1−メトキシ−2−プロパノール、ジメチルスルホキシド、ジメチルスルホン又はジメチルホルムアミドである、請求項7記載の方法。
- 前記遊離剤が前記疎水性薬物の類似体である、請求項1記載の方法。
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