Are Circulating Metabolites Important in Pharmacokinetic Drug-Drug Interactions? A Retroanalysis of Clinical Data
文献类型：期刊论文
| 作者 | Zhao, Yuan-Sheng2; Chen, Feng3; Li, Li1 |
| 刊名 | CURRENT DRUG METABOLISM
 |
| 出版日期 | 2014 |
| 卷号 | 15期号:8页码:767-790 |
| 关键词 | Human drug metabolites inhibitory roles official investigation guidance pharmacokinetic drug-drug interactions |
| ISSN号 | 1389-2002 |
| 文献子类 | Article |
| 英文摘要 | Pharmacokinetic (PK) drug-drug interactions (DDIs) give rise to adverse events and/or reduced efficacy. Comprehensive, systematic and mechanistic approaches have been applied in the evaluation, propagation and management of the interaction potential of a new drug during its development and clinical use. However, the role of drug metabolite(s) in DDIs was not extensively investigated. Recently, regulatory bodies have proposed that metabolites at >= 25% of the parent drug's area under the time-concentration curve (AUC) and/or >10% of the total drug-related exposure should be investigated in vitro for DDI potential. This review aimed to identify the drugs and their metabolites meeting the official guidance's criteria for DDI studies, and to assess whether the eligible drugs caused significant clinical PK DDIs and furthermore whether the metabolites contributed to the observed PK DDIs. Eighty seven drugs were eligible and nearly 45% (39/87) drugs were not reported with clinical PK DDIs. About 78% (68/87) drugs demonstrated inhibitory and/or inducible effects on drug-metabolizing enzymes and/or drug transporters; while the remaining 19 (22%) parent drugs showed no such effects. For 8 drugs (similar to 9%), their metabolites were able to inhibit and/or induce the drug-metabolizing enzymes and drug transporters. Three drug-metabolite pairs were found to be the perpetrators of the complex PK DDIs. Our retrospective analysis suggested that the PK DDI risks caused by metabolites alone might not be high, which is somewhat different from the conclusions from some other studies on this topic. However, circulating drugs often work as perpetrators of PK DDIs suggesting a need for more efforts to characterize the roles of their metabolites. Our study should be of value in stimulating discussions among the scientific community on this important topic. |
| WOS关键词 | NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; STEADY-STATE PHARMACOKINETICS ; HEALTHY MALE-VOLUNTEERS ; PROTON PUMP INHIBITORS ; HUMAN LIVER-MICROSOMES ; SAFETY TESTING MIST ; IN-VIVO ; P-GLYCOPROTEIN ; PLASMA-CONCENTRATIONS ; PHARMACODYNAMIC INTERACTIONS |
| 资助项目 | National Natural Science Fund of China[81460629] ; National Natural Science Fund of China[81102878] ; National Science Fund of Hainan Province[812189] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000350280800003 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277245]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Chen, Feng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China; 2.Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY USA 3.Hainan Med Univ, Coll Pharm, Hainan Prov Key Lab R&D Trop Herbs, Haikou, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhao, Yuan-Sheng,Chen, Feng,Li, Li. Are Circulating Metabolites Important in Pharmacokinetic Drug-Drug Interactions? A Retroanalysis of Clinical Data[J]. CURRENT DRUG METABOLISM,2014,15(8):767-790. |
| APA | Zhao, Yuan-Sheng,Chen, Feng,&Li, Li.(2014).Are Circulating Metabolites Important in Pharmacokinetic Drug-Drug Interactions? A Retroanalysis of Clinical Data.CURRENT DRUG METABOLISM,15(8),767-790. |
| MLA | Zhao, Yuan-Sheng,et al."Are Circulating Metabolites Important in Pharmacokinetic Drug-Drug Interactions? A Retroanalysis of Clinical Data".CURRENT DRUG METABOLISM 15.8(2014):767-790. |
入库方式： OAI收割
来源：上海药物研究所
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