Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs
文献类型：期刊论文
| 作者 | Zhou, Xin; Gao, Zhi-wei ; Meng, Jian; Chen, Xiao-yan; Zhong, Da-fang
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| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2013-11 |
| 卷号 | 34期号:11页码:1420-1426 |
| 关键词 | GLS4 ketoconazole rifampicin CYP3A drug-drug interaction hepatitis B virus |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.76 |
| 文献子类 | Article |
| 英文摘要 | Aim: To investigate the metabolism of GLS4, a heteroaryldihydropyrimidine compound with anti-hepatitis B virus activity, in dog and human liver microsomes in vitro and evaluate the effects of ketoconazole (a potent CYP3A inhibitor) or rifampicin (a potent CYP3A inducer) on GLS4 pharmacokinetics in dogs. Methods: Dog and human liver microsomes and CYP3A4 were incubated with [C-14] GLS4 for 15 min and then analyzed using a HPLC-dynamic online radio flow detection method. Two groups of beagle dogs were used for in vivo studies. Group A were orally administered a single dose of GLS4 (15 mg/kg) with or without ketoconazole pretreatment (100 mg/d for 8 consecutive days). Group B were orally administered a single dose of GLS4 (15 mg/kg) with or without rifampicin pretreatment (100 mg/d for 8 consecutive days). Plasma was sampled after GLS4 dosing. GLS4 concentrations were determined by HPLC-tandem mass spectrometry. Results: The metabolic profile of [C-14] GLS4 in human and dog liver microsomes and CYP3A4 was similar. The major metabolites were morpholine N-dealkylated GLS4 and morpholine N,N-di-dealkylated GLS4. Pretreatment with ketoconazole or rifampicin significantly affected the plasma concentrations of GLS4 in dogs: ketoconazole increased the area under the concentration-time curve from 0 to infinity and peak concentration of GLS4 by 4.4 and 3.3 folds, respectively, whereas rifampicin decreased these parameters by 88.5% and 83.2%, respectively. Conclusion: GLS4 is a sensitive substrate of CYP3A. CYP3A inhibitors or inducers cause considerable change of GLS4 plasma concentrations in dogs, which should be considered in clinical practice. |
| WOS关键词 | IN-VITRO ; CYTOCHROME-P450 3A4 ; ADEFOVIR-DIPIVOXIL ; BEAGLE DOGS ; INHIBITION ; METABOLISM ; REPLICATION ; NIFEDIPINE ; EXPRESSION ; LAMIVUDINE |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4966496 |
| WOS记录号 | WOS:000326680500008 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277398]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Zhong, Da-fang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Xin,Gao, Zhi-wei,Meng, Jian,et al. Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs[J]. ACTA PHARMACOLOGICA SINICA,2013,34(11):1420-1426. |
| APA | Zhou, Xin,Gao, Zhi-wei,Meng, Jian,Chen, Xiao-yan,&Zhong, Da-fang.(2013).Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs.ACTA PHARMACOLOGICA SINICA,34(11),1420-1426. |
| MLA | Zhou, Xin,et al."Effects of ketoconazole and rifampicin on the pharmacokinetics of GLS4, a novel anti-hepatitis B virus compound, in dogs".ACTA PHARMACOLOGICA SINICA 34.11(2013):1420-1426. |
入库方式： OAI收割
来源：上海药物研究所
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