1999 年度実績報告書

治療薬の代謝に関する6種類の酵素活性測定法の開発と薬効・副作用発現機構の研究

研究課題

研究課題/領域番号	11672267
研究機関	熊本大学
研究代表者	石崎高志熊本大学, 薬学研究科, 教授 (50158747)
キーワード	薬物代謝酵素 / caffeine / phenotyping / 遺伝的多型 / cytochrome P450 / N-acetyltransferase / xanthine oxidase / flavin monooxygenase
研究概要	本研究の目的は、日本人健常成人志願者を対象としてcaffeineとphenytoin(PHT)による安全で簡便なcocktail phenotyping testを確立し、治療薬代謝に関わる6種類の酵素のphenotypingとgenotypingによって日本人における各酵素の遺伝子変異頻度を明らかにすることである。今年度は、倫理委員会の承認を受けたプロトコールに従い、研究者29人が、PHT100mg、caffeine 150mg、PHT 100mg+caffeine 150mgを一週間のwash-out期間をおきながらLatin-square法によって就寝前に服用して翌日の早朝尿を採取した。さらに尿中のPTHとその代謝物:R-p-[5-(d-hydroxyphenyl)-5-phenylhydantoin](R-p-HPPH)、S-p-HPPH、及びcaffeineの代謝物:1,7-dimetyl uric acid(17DMU)、1-methyl xanthine(1MX)、1-methyl uric acid(1MU)、5-acetyl-6-amino-3-methyluracil(AAMU)の測定法を確立し、再現性、相互作用の有無について検討した。その結果、本カクテル法では、cytochrome P450(CYP) 1A2,N-acetyltransferase,xanthine oxidase,flavin monooxygenaseの活性測定が可能であった。一方、本法でCYP2C9,CYP2C19の活性を測定することは困難であったが、これらの酵素のgenotyping法は確立した。以上の結果は、4月の2000年世界薬学会議(サンフランシスコ)で発表する。次年度は、健常者200人を対象としてcaffeineのみによる4種類の薬物代謝酵素のphenotypingを行うとともに、各種酵素のgenotyping法を確立して日本人における各酵素の遺伝子変異頻度を明らかにする。また参考論文に示すように、我々は薬物治療効果と薬物代謝酵素の遺伝的多型に関する研究も本研究と平行して行っており、今後、各種疾患(adverse drug reactions、肝、腎障害、アトピー性疾患)患者や欧米人においてもcaffeine phenotyping testを行って、病態下における薬物代謝酵素活性や、その遺伝的多型と疾患の関連性などについて研究を展開していく予定である。

研究成果
(17件)

すべてその他

すべて文献書誌 (17件)

[文献書誌] Kudo S,Okumura H,Miyamoto G and Ishizaki T: "Cytochrome P-450 isoforms involved in carboxylic acid ester cleavage of Hantzsch pyridine ester of pranidipine"Drug Metab Dispos. 27. 303-308 (1999)
[文献書誌] Furuta T,.,et al.: "CYP2C19 genotype status and effect of omeprazole in intragastric pH in humans."Clin Pharmacol Ther. 65. 552-561 (1999)
[文献書誌] Zhao X-J,Koyama E and Ishizaki T: "An in vitro study on the metabolism and possible drug interactions of rokitamycin,a macrolide antibiotic,using human liver microsomes."Drug Metab Dispos. 27. 776-785 (1999)
[文献書誌] Kaneko A,.,et al.: "Intrinsic efficacy of proguanil against flaciparum and vivax malaria independent of the metabolite cycloguanil."J Inf Dis. 179. 974-979 (1999)
[文献書誌] Kaneko A,Bergqvist Y,Taleo G,Kobayakawa T,Ishizaki T and Bjorkman A: "Proguanil disposition and toxicity in malaria patients from Vamuatu with high frequencies of CYP2C19 mutations."Pharmacogenetics. 9. 317-326 (1999)
[文献書誌] Ishizaki T,and Horai Y: "Review article:cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole."Aliment Pharmacol ther. 13. 27-36 (1999)
[文献書誌] Hamaoka N,Oda Y,Hase I,Mizutani K,Nakamoto T,Ishizaki T and Asada A: "Propofol decreases the clearance of midazolam by inhibiting CYP3A4:An in vivo and in vitro study."Clin Pharmacol Ther. 66. 110-117 (1999)
[文献書誌] Zhao X-J and Ishizaki T: "An in vitro study on rokitamycin metabolism and its possible drug interactions by rat liver microsomes."J Pharm Pharmacol. 51. 1167-1174 (1999)
[文献書誌] Suzuki A .,et al.: "Identification of human CYP isoforms involved in the metabolism of R(+)-and S(-)-gallopamil:Utility of in vitro disappearance rate."Drug Metab Dispos. 27. 1254-1259 (1999)
[文献書誌] Furutra T .,et al.: "Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans."Clin Pharmacol Ther. 66. 265-271 (1999)
[文献書誌] Kudo S and Ishizaki T: "Pharmacokinetics of haloperidol. An update."Clin Pharmacokinet. 37. 435-456 (1999)
[文献書誌] Terazaki H .,et al.: "A novel compound heterozygote (FAP ATTR Arg104His/ATTR Va130Met)with high serum transthreitin(TTR)and retinol binding protein(RBP)levels."Biochem Biophys Res Commun. 264. 365-370 (1999)
[文献書誌] Chida M .,et al.: "Genetic polymorphism of CYP2D6 in the Japanese population."Pharmacogenetics. 9. 601-605 (2000)
[文献書誌] Nakagawa K and Ishizaki T: "Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine."Pharmacik Ther. (in press). (2000)
[文献書誌] Obayashi K .,et al.: "Effect of sildenafil citrate(Viagra)on erectile dysfunction in a patient with familial amyloidotic polyneuropathy ATTR Va130Met."J Auton Nervous Sys. (in press). (2000)
[文献書誌] Kaneko A .,et al.: "High and variable frequencies of CYP2C19 mutations:Medical consequenes of poor drug metabolism in Vanuatu and other Pacific Islands."Pharmacogenetics. (in press). (2000)
[文献書誌] Uno T,Ohkubo T,Sugawara K,Higashiyama A,Motomura S and Ishizaki T: "Effects of grapefruit juice on the stereoselective disposition of nicardipine in human:An evidence for dominant presystemic elimination at the gut site."Eur J Clin Pharmacol.. (in press). (2000)

1999 年度 実績報告書

治療薬の代謝に関する6種類の酵素活性測定法の開発と薬効・副作用発現機構の研究

研究代表者

石崎 高志 熊本大学, 薬学研究科, 教授 (50158747)

研究成果

[文献書誌] Kudo S,Okumura H,Miyamoto G and Ishizaki T: "Cytochrome P-450 isoforms involved in carboxylic acid ester cleavage of Hantzsch pyridine ester of pranidipine"Drug Metab Dispos. 27. 303-308 (1999)

[文献書誌] Furuta T,.,et al.: "CYP2C19 genotype status and effect of omeprazole in intragastric pH in humans."Clin Pharmacol Ther. 65. 552-561 (1999)

[文献書誌] Zhao X-J,Koyama E and Ishizaki T: "An in vitro study on the metabolism and possible drug interactions of rokitamycin,a macrolide antibiotic,using human liver microsomes."Drug Metab Dispos. 27. 776-785 (1999)

[文献書誌] Kaneko A,.,et al.: "Intrinsic efficacy of proguanil against flaciparum and vivax malaria independent of the metabolite cycloguanil."J Inf Dis. 179. 974-979 (1999)

[文献書誌] Kaneko A,Bergqvist Y,Taleo G,Kobayakawa T,Ishizaki T and Bjorkman A: "Proguanil disposition and toxicity in malaria patients from Vamuatu with high frequencies of CYP2C19 mutations."Pharmacogenetics. 9. 317-326 (1999)

[文献書誌] Ishizaki T,and Horai Y: "Review article:cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole."Aliment Pharmacol ther. 13. 27-36 (1999)

[文献書誌] Hamaoka N,Oda Y,Hase I,Mizutani K,Nakamoto T,Ishizaki T and Asada A: "Propofol decreases the clearance of midazolam by inhibiting CYP3A4:An in vivo and in vitro study."Clin Pharmacol Ther. 66. 110-117 (1999)

[文献書誌] Zhao X-J and Ishizaki T: "An in vitro study on rokitamycin metabolism and its possible drug interactions by rat liver microsomes."J Pharm Pharmacol. 51. 1167-1174 (1999)

[文献書誌] Suzuki A .,et al.: "Identification of human CYP isoforms involved in the metabolism of R(+)-and S(-)-gallopamil:Utility of in vitro disappearance rate."Drug Metab Dispos. 27. 1254-1259 (1999)

[文献書誌] Furutra T .,et al.: "Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans."Clin Pharmacol Ther. 66. 265-271 (1999)

[文献書誌] Kudo S and Ishizaki T: "Pharmacokinetics of haloperidol. An update."Clin Pharmacokinet. 37. 435-456 (1999)

[文献書誌] Terazaki H .,et al.: "A novel compound heterozygote (FAP ATTR Arg104His/ATTR Va130Met)with high serum transthreitin(TTR)and retinol binding protein(RBP)levels."Biochem Biophys Res Commun. 264. 365-370 (1999)

[文献書誌] Chida M .,et al.: "Genetic polymorphism of CYP2D6 in the Japanese population."Pharmacogenetics. 9. 601-605 (2000)

[文献書誌] Nakagawa K and Ishizaki T: "Therapeutic relevance of pharmacogenetic factors in cardiovascular medicine."Pharmacik Ther. (in press). (2000)

[文献書誌] Obayashi K .,et al.: "Effect of sildenafil citrate(Viagra)on erectile dysfunction in a patient with familial amyloidotic polyneuropathy ATTR Va130Met."J Auton Nervous Sys. (in press). (2000)

[文献書誌] Kaneko A .,et al.: "High and variable frequencies of CYP2C19 mutations:Medical consequenes of poor drug metabolism in Vanuatu and other Pacific Islands."Pharmacogenetics. (in press). (2000)

[文献書誌] Uno T,Ohkubo T,Sugawara K,Higashiyama A,Motomura S and Ishizaki T: "Effects of grapefruit juice on the stereoselective disposition of nicardipine in human:An evidence for dominant presystemic elimination at the gut site."Eur J Clin Pharmacol.. (in press). (2000)

1999 年度実績報告書

石崎高志熊本大学, 薬学研究科, 教授 (50158747)