A Simplified Diagnostic Approach for Estimating in vivo Hepatic Drug Clearance ; Its Preliminary Application for the Drug Caffeine, Using CYP1A Probe in a Rat Model
スポンサーリンク
概要
- 論文の詳細を見る
A novel approach for identifying the inter-individual variation in hepatic clearance was investigated based on physiological pharmacokinetic studies and estimations of the amount of cytochrome P450 (CYP) in vivo. This approach is referred to as the PKCYP-test. In order to correlate in. vitro-in vivo metabolic parameters, we examined the apparent liver-to-blood free concentration gradient in vivo (qg). We confirmed the validity of the PKCYP-test using acetanilide and caffeine as the CYP1A2 probe and test drug, respectively, in rats. Increased liver enzyme levels were induced in rats by the administration of 3-methylcholanthrene (MC) (MC-treated rats). We observed a 5-fold variation in the total body clearance (CL_<tot>) of acetanilide, and a 10-fold variation in the CL_<tot>, of caffeine in control versus the MC-treated rats. Furthermore, the quantitation of CYP1A2 protein by Western blotting of liver microsomal protein, using a specific antibody, revealed a 20-fold increase in the MC-treated rats. The qg values were determined as the ratio of the in vivo-in vitro clearances. By considering the qg value of the control rats, we were able to predict the level of CYP1A2 in the MC-treated rats based on the CL_<tot> value of acetanilide. The CL_<tot> values for caffeine in the MC-treated rats, as estimated from the predicted level of CYP1A2, closely correlated with the observed value. In conclusion, we were able to show that it is possible to predict inter-individual differences in the metabolic clearance of patients with different amounts of CYP based on the specific qg value of a drug.
- 日本医療薬学会の論文
- 2000-10-10
著者
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Kose Matsunaga
Department Of Practical Pharmacy Kyoritsu College Of Pharmacy
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Nakashima E
Dep. Of Pharmaceutics Kyoritsu Univ. Of Pharmacy
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Nakashima Emi
Faculty Of Pharmaceutical Sciences Kanazawa University
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Nakashima Emi
Department Of Pharmaceutics Kyoritsu University Of Pharmacy
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Nakashima Emi
Department Of Pediatrics:hospital Pharmacy:and Faculty Of Pharmaceutical Sciences University Of Kana
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Iizasa H
Kyoritsu Univ. Pharmacy Tokyo Jpn
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Iizasa Hisashi
Department Of Pharmaceutics Kyoritsu University Of Pharmacy
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HATTORI Kenji
Department of Otolaryngology, Sumitomo Hospital
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Takahashi Atsushi
Division Of Pharmacology National Institute Of Hygienic Sciences
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Nakashima Emi
Faculty Of Pharmaceutical Sciences And Hospital Pharmacy Kanazawa University
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Hattori Kenji
Department Of Pharmaceutics Kyoritsu College Of Pharmacy
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Matsunaga Noriko
Department Of Practical Pharmacy Kyoritsu College Of Pharmacy
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TAKANAKA Akira
The Organization for Pharmaceutical Safety and Research
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FUKUHARA MORIO
Department of Pharmaceutical Sciences, National Institute of Public Health
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Fukuhara M
Department Of Pharmaceutical Sciences National Institute Of Public Health
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Fukuhara Morio
Department Of Pharmaceutical Sciences
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Takanaka Akira
Division Of Pharmacology Bsrc National Institute Of Hygienic Sciences
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Takanaka A
National Inst. Hygienic Sciences Tokyo Jpn
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中島 恵美
Department Of Pharmaceutics Kyoritsu University Of Pharmacy
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Fukuhara Morio
Department Of Pharmaceutical Sciences National Institute Of Public Health
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Takahashi A
Division Of Pharmacology Bsrc National Institute Of Hygienic Sciences
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Hattori Kenji
Department Of Otolaryngology Sumitomo Hospital
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HATTORI Kenji
Department of Material Physics, Faculty of Engineering Science, Osaka University
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