2000 Fiscal Year Annual Research Report

薬物の代謝に関与するP450各分子種の寄与率の定量的評価

Research Project

Project/Area Number	11771468
Research Institution	Kanazawa University
Principal Investigator	中嶋美紀金沢大学, 薬学部, 助手 (70266162)
Keywords	薬物相互作用 / 薬物代謝 / チトクロムP450 / CYP / ヒト肝ミクロソーム
Research Abstract	抗不整脈薬であるアミオダロンはヒトにおいて主にN-脱エチル化を受けてデスエチルアミオダロンへと代謝される。本研究では、この反応を触媒するヒトP450分子種の寄与率を検討した。バキュロウイルス発現系ミクロソームを用いたアミオダロンN-脱エチル化酵素活性のクリアランスはCYP3A4が最も高く、ついでCYP2C8、CYP1A2、CYP2D6、CYP2C19の順であった。ヒト肝ミクロソームにおけるアミオダロンN-脱エチル化酵素活性はCYP3A抗体およびCYP3A4の阻害剤であるケトコナゾールによって強く阻害され、また、CYP2C8の阻害剤であるクエルセチンおよびCYP1A2の阻害剤であるフラボキサミンによっても阻害された。6検体のヒト肝ミクロソームにおけるアミオダロンN-脱エチル化酵素活性は低基質濃度ではCYP2C8の特異的酵素活性であるパクリタキセル6α-水酸化酵素活性と有意に相関し、高基質濃度ではCYP3A4の特異的酵素活性であるテストステロン6β-水酸化酵素活性と有意に相関した。発現系ミクロソームとヒト肝ミクロソームにおけるP450各分子種の特異的酵素活性の比(Relative Activity Factor,RAF)を用いてアミオダロンN-脱エチル化に関与する分子種の寄与率を算出したところ、低濃度域ではCYP2C8の寄与率が大きく、CYP3A4と同等またはそれ以上にもなる検体も認められた。高濃度域ではCYP3A4の寄与がほとんどであり、CYP1A2、CYP2D6、CYP2C19の寄与は小さいことを明らかにした。

Research Products

(6 results)

All Other

All Publications (6 results)

[Publications] Ohyama K,Nakajima M,Nakamura S,Shimada N,Yamazaki H,Yokoi T.: "A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation : an approach to predoct the contribution with relative activity factor."Drug Metabolism and Disposition. 28・11. 1303-1310 (2000)
[Publications] Ohyama K,Nakajima M,Suzuki M,Shimada N,Yamazaki H,Yokoi T.: "Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities : prediction of in vivo drug ineteractions"British Journal of Clinical Pharmacology. 49・3. 244-253 (2000)
[Publications] Nakajima M,Yamagishi S-I,Yamamoto H,Yamamoto T,Kuroiwa Y,Yokoi T.: "Deficient cotinine formation from nicotine is ascribed to the whole deletion of the CYP2A6 gene."Clinical Pharmacology and Therapeutics. 67・1. 57-69 (2000)
[Publications] Nakajima M,Yamamoto T,Kuroiwa Y,Yokoi T.: "Improved highly sensitive method for determination of nicotine and cotinine in human plasma by high-performance liquid chromatography."Journal of Chromatography B. 742・1. 211-215 (2000)
[Publications] Katoh M,Nakajima M,Shimada N,Yamazaki H,Yokoi T.: "Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists : prediction of in vivo drug-drug interactions."European Journal of Clinical Pharmacology. 55・11-12. 843-852 (2000)
[Publications] Katoh M,Nakajima M,Yamazaki H,Yokoi T.: "Inhibitory potencies of 1,4-dihydroxypyridine calcium antagonists to P-glycoprotein-mediated transport : comparison with the effects on CYP3A4."Pharmaceutical Research. 17・10. 1189-1197 (2000)

2000 Fiscal Year Annual Research Report

薬物の代謝に関与するP450各分子種の寄与率の定量的評価

Principal Investigator

中嶋 美紀 金沢大学, 薬学部, 助手 (70266162)

Research Products

[Publications] Ohyama K,Nakajima M,Nakamura S,Shimada N,Yamazaki H,Yokoi T.: "A significant role of human cytochrome P450 2C8 in amiodarone N-deethylation : an approach to predoct the contribution with relative activity factor."Drug Metabolism and Disposition. 28・11. 1303-1310 (2000)

[Publications] Ohyama K,Nakajima M,Suzuki M,Shimada N,Yamazaki H,Yokoi T.: "Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities : prediction of in vivo drug ineteractions"British Journal of Clinical Pharmacology. 49・3. 244-253 (2000)

[Publications] Nakajima M,Yamagishi S-I,Yamamoto H,Yamamoto T,Kuroiwa Y,Yokoi T.: "Deficient cotinine formation from nicotine is ascribed to the whole deletion of the CYP2A6 gene."Clinical Pharmacology and Therapeutics. 67・1. 57-69 (2000)

[Publications] Nakajima M,Yamamoto T,Kuroiwa Y,Yokoi T.: "Improved highly sensitive method for determination of nicotine and cotinine in human plasma by high-performance liquid chromatography."Journal of Chromatography B. 742・1. 211-215 (2000)

[Publications] Katoh M,Nakajima M,Shimada N,Yamazaki H,Yokoi T.: "Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists : prediction of in vivo drug-drug interactions."European Journal of Clinical Pharmacology. 55・11-12. 843-852 (2000)

[Publications] Katoh M,Nakajima M,Yamazaki H,Yokoi T.: "Inhibitory potencies of 1,4-dihydroxypyridine calcium antagonists to P-glycoprotein-mediated transport : comparison with the effects on CYP3A4."Pharmaceutical Research. 17・10. 1189-1197 (2000)

中嶋美紀金沢大学, 薬学部, 助手 (70266162)