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Examination of the Impact of CYP3A4/5 on Drug-Drug Interaction between Schizandrol A/Schizandrol B and Tacrolimus (FK-506): A Physiologically Based Pharmacokinetic Modeling Approach.
He, Qingfeng; Bu, Fengjiao; Wang, Qizhen; Li, Min; Lin, Jiaying; Tang, Zhijia; Mak, Wen Yao; Zhuang, Xiaomei; Zhu, Xiao; Lin, Hai-Shu; Xiang, Xiaoqiang.
Affiliation
  • He Q; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Bu F; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Wang Q; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Li M; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Lin J; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Tang Z; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Mak WY; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • Zhuang X; Clinical Research Centre, Hospital Pulau Pinang, Pinang 10450, Malaysia.
  • Zhu X; Institute for Clinical Research, National Institute of Health, Shah Alam 40170, Malaysia.
  • Lin HS; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
  • Xiang X; Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.
Int J Mol Sci ; 23(9)2022 Apr 19.
Article in En | MEDLINE | ID: mdl-35562875
Schizandrol A (SZA) and schizandrol B (SZB) are two active ingredients of Wuzhi capsule (WZC), a Chinese proprietary medicine commonly prescribed to alleviate tacrolimus (FK-506)-induced hepatoxicity in China. Due to their inhibitory effects on cytochrome P450 (CYP) 3A enzymes, SZA/SZB may display drug-drug interaction (DDI) with tacrolimus. To identify the extent of this DDI, the enzymes' inhibitory profiles, including a 50% inhibitory concentration (IC50) shift, reversible inhibition (RI) and time-dependent inhibition (TDI) were examined with pooled human-liver microsomes (HLMs) and CYP3A5-genotyped HLMs. Subsequently, the acquired parameters were integrated into a physiologically based pharmacokinetic (PBPK) model to quantify the interactions between the SZA/SZB and the tacrolimus. The metabolic studies indicated that the SZB displayed both RI and TDI on CYP3A4 and CYP3A5, while the SZA only exhibited TDI on CYP3A4 to a limited extent. Moreover, our PBPK model predicted that multiple doses of SZB would increase tacrolimus exposure by 26% and 57% in CYP3A5 expressers and non-expressers, respectively. Clearly, PBPK modeling has emerged as a powerful approach to examine herb-involved DDI, and special attention should be paid to the combined use of WZC and tacrolimus in clinical practice.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tacrolimus / Cytochrome P-450 CYP3A Type of study: Prognostic_studies Limits: Humans Language: En Journal: Int J Mol Sci Year: 2022 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tacrolimus / Cytochrome P-450 CYP3A Type of study: Prognostic_studies Limits: Humans Language: En Journal: Int J Mol Sci Year: 2022 Document type: Article Affiliation country: Country of publication: