BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2017
·Vol. 122
·期 3
·331-340
·
IF 3.176
Hongyan Zhang,Fengjiao Bu,Lei Li,Zheng Jiao,Guo Ma,Weimin Cai,Xiaomei Zhuang,Hai-Shu Lin,Jae-Gook Shin,Xiaoqiang Xiang
Schisantherin A and schisandrin A, the most abundant active ingredients of Wuzhi capsule, are known to inhibit tacrolimus metabolism by inhibiting CYP3A4/5. We aimed to predict the contribution of schisantherin A and schisandrin A to drug–drug interaction (DDI) between Wuzhi capsule and tacrolimus using physiologically-based pharmacokinetic (PBPK) modelling. Firstly, the inhibition mechanism of schisantherin A and schisandrin A on CYP3A4/5 was investigated. Thereafter, PBPK models of schisantherin A, schisandrin A and tacrolimus were established. Finally, tacrolimus pharmacokinetics were evaluated after the combined use with schisantherin A or schisandrin A. The blood area under the curve (AUC) of tacrolimus increased 1.77- and 2.61-fold after a single dose and multiple doses of schisantherin A, respectively. Meanwhile, schisandrin A inhibited tacrolimus metabolism to a smaller extent. Also, it showed that mechanism-based inhibition (MBI) played a more important role in DDI than reversible inhibition after long-term administration, while reversible inhibition was comparable to MBI after single-dose administration. In conclusion, we utilized PBPK modelling to quantify the contribution of schisantherin A and schisandrin A to DDI between tacrolimus and Wuzhi capsule. This may provide more insights for the rational use of this drug combination.
研究领域:
药理学
·
临床药学
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NUTRITION & FOOD RESEARCH
·
2013
·Vol. 57
·期 5
·877-885
·
IF 4.31
Zhong-Jian Chen,Yan-Qing Dai,Si-Si Kong,Fei-Feng Song,Li-Ping Li,Jian-Feng Ye,Ru-Wei Wang,Su Zeng,Hui Zhou,Hui-Di Jiang
Scope The study aimed to investigate the regioselectivity of methylation of luteolin (3′,4′,5,7-tetrahydroxyflavone) in human in vitro and in vivo. Methods and results Recombinant human catechol- O -methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3′)- and para (4′)- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CL int (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin. Conclusion Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.
研究领域:
药理学
·
生物化学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 9
·4485
·
IF 6.208
Qingfeng He,Fengjiao Bu,Qizhen Wang,Min Li,Jiaying Lin,Zhijia Tang,Wen Yao Mak,Xiaomei Zhuang,Xiao Zhu,Hai-Shu Lin,Xiaoqiang Xiang
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.Keywords:physiologically based pharmacokinetic (PBPK);Wuzhi capsule (WZC);tacrolimus (FK-506);CYP3A5 polymorphism;drug–drug interaction (DDI);schizandrol A (SZA);schizandrol B (SZB)
研究领域:
药理学
·
临床医学
·
中药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）