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
International Journal of Molecular Sciences
; 23(9):4485, 2022.
Article
in English
| ProQuest Central | ID: covidwho-1842816
ABSTRACT
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.
Chemistry--Organic Chemistry; physiologically based pharmacokinetic (PBPK); Wuzhi capsule (WZC); tacrolimus (FK-506); CYP3A5 polymorphism; drug–drug interaction (DDI); schizandrol A (SZA); schizandrol B (SZB); Drug interaction; Simulation; Drug interactions; Oral administration; Pharmacokinetics; Cytochrome P450; Modelling; Enzymes; Cytochromes P450; Pharmacology; Microsomes; Metabolism; Chinese medicine; Tacrolimus; Polymorphism; Drug dosages; COVID-19; China
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Collection:
Databases of international organizations
Database:
ProQuest Central
Type of study:
Experimental Studies
Language:
English
Journal:
International Journal of Molecular Sciences
Year:
2022
Document Type:
Article
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