We aim to describe the influence of principal ingredients of Wuzhi capsule, schisandrin A (SIA) and schisantherin A (STA), on the pharmacokinetics of cyclosporin A (CsA) and to quantify the herb–drug interactions (HDIs) between SIA, STA, and CsA. CsA is a first-line immunosuppressant for anti-rejection therapy after solid organ transplantation, while narrow therapeutic window associated with strong hepatotoxicity largely limited its use. Wuzhi capsule, a liver-protective drug, was approved for coadministration with CsA to reduce the hepatotoxicity. There are few studies exploring HDIs of CsA when coadministered with Wuzhi capsule. The essential adjusted physicochemical data and pharmacokinetic parameters of SIA, STA, and CsA were collected. Then physiologically based pharmacokinetic (PBPK) models of SIA, STA, and CsA were built and verified in healthy subjects using Simcyp respectively. The refined PBPK models were used to estimate potential HDIs between CsA and SIA, STA. The simulated plasma concentration–time curves of CsA, SIA, and STA were in good accordance with the observed profiles respectively. CsA pharmacokinetics were improved after coadministration. After a single dose and multiple doses, the area under the plasma concentration–time curve (AUC) of CsA was increased by 47% and 226% when coadministered with STA, respectively, and by 8% and 36% when coadministered with SIA, respectively. PBPK models sufficiently described the pharmacokinetics of CsA, SIA, and STA. Compared with SIA, STA inhibited CsA metabolism to a greater extent. Our result revealed the dose of CsA can be reduced to maintain similar profile when used concomitantly with Wuzhi capsule.
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Fu R, Tajima S, Suetsugu K, et al. Biomarkers for individualized dosage adjustments in immunosuppressive therapy using calcineurin inhibitors after organ transplantation. Acta Pharmacol Sin. 2018;1.
Fredericks S, Jorga AM, Macphee IAM, et al. Multi-drug resistance gene-1 (MDR-1) haplotypes and the CYP3A5*1 genotype have no influence on ciclosporin dose requirements as assessed by C0 or C2 measurements. Clin Transpl. 2007;21(2):252–7.
Liu F, Mao JH. Calcineurin inhibitors and nephrotoxicity in children. World J Pediatr. 2018;14(2):121–6.
Xiao-Qin W, Lan W, Yuan-Chao T, et al. Traditional Chinese medicine for refractory nephrotic syndrome: strategies and promising treatments. Evid Based Complement Alternat Med. 2018;2018:1–11.
Hua W, Haijun M, Yunlei Y, et al. Validation of an LC-MS/MS method for quantitative analysis of the 5 bioactive components of Wuzhi capsule in human plasma samples. Ther Drug Monit. 2014;36(6):781–8.
Sun Z, Ren M, Wu Q, du X. Co-administration of Wuzhi capsules and tacrolimus in patients with idiopathic membranous nephropathy: clinical efficacy and pharmacoeconomics. Int Urol Nephrol. 2014;46(10):1977–82.
Qin XL, Yu T, Li LJ, Wang Y, Gu HM, Wang YT, et al. Effect of long-term co-administration of Wuzhi tablet (Schisandra sphenanthera extract) and prednisone on the pharmacokinetics of tacrolimus. Phytomedicine. 2013;20(3–4):375–9.
Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol. 2007;64(4):469–75.
Zhang H, Bu F, Li L, Jiao Z, Ma G, Cai W, et al. Prediction of drug–drug interaction between tacrolimus and principal ingredients of Wuzhi capsule in Chinese healthy volunteers using physiologically-based pharmacokinetic modelling. Basic Clin Pharmacol Toxicol. 2018;122(3):331–40.
Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract. Drug Metab Dispos. 2004;32(12):1351–8.
Xin HW, Li Q, Wu XC, He Y, Yu AR, Xiong L, et al. Effects of Schisandra sphenanthera extract on the blood concentration of tacrolimus in renal transplant recipients. Eur J Clin Pharmacol. 2011;67(12):1309–11.
Wu Q, Kamil K. Metabolic pathway of cyclosporine A and its correlation with nephrotoxicity. Curr Drug Metab. 2019;20(2):84–90.
Kaya H, Koc A, Sogut S, Duru M, Yilmaz HR, Uz E, et al. The protective effect of N-acetylcysteine against cyclosporine A-induced hepatotoxicity in rats. J Appl Toxicol. 2008;28(1):15–20.
Kahan BD, Wideman CA, Reid M, Gibbons S, Jarowenko M, Flechner S, et al. The value of serial serum trough cyclosporine levels in human renal transplantation. Transplant Proc. 1984;16(5):1195–9.
Wang C, Lu KP, Chang Z, et al. Association of CYP3A4* 1B genotype with cyclosporin A pharmacokinetics in renal transplant recipients: a meta-analysis. Gene. 2018;664:44–9.
Capron A, Haufroid V, Wallemacq P. Intra-cellular immunosuppressive drugs monitoring: a step forward towards better therapeutic efficacy after organ transplantation? Pharmacol Res. 2016;111:610–8.
Vine W, Bowers LD, Shaw LM. Cyclosporine: structure, pharmacokinetics, and therapeutic drug monitoring. CRC Crit Rev Clin Lab Sci. 1987;25(4):275–312.
Mikus G, Schöwel V, Drzewinska M, Rengelshausen J, Ding R, Riedel KD. Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir. Clin Pharmacol Ther. 2006;80:126–35.
Zhang M, Zheng J, Deng C, Song XM, Han L. Vinegar steam effect on oil–water partition coefficients of Fructus Schisandrae sphenantherae. Lishizhen Med Mater Med Res. 2012;23:2695–6.
Liang Y, Zhou YY, Liu YN, Guan TY, Zheng X, Dai C, et al. Study on the plasma protein binding rate of Schisandra lignans based on the LC-IT-TOF/MS technique with relative quantitative analysis. Chin J Nat Med. 2013;11:442–8.
Qin XL, Chen X, Zhong GP, Fan XM, Wang Y, Xue XP, et al. Effect of tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp. Phytomedicine. 2014;21:766–72.
Sun F, Lee L, Zhang Z, Wang X, Yu Q, Duan XQ, et al. Preclinical pharmacokinetic studies of 3-deazaneplanocin a, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus? Eur J Pharm Sci. 2015;77:290–302.
Jones DHM, Parrott N, Jorga K, et al. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet. 2006;45(5):511–42.
Perdaems N, Blasco H, Vinson C, Chenel M, Whalley S, Cazade F, et al. Predictions of metabolic drug–drug interactions using physiologically based modelling. Clin Pharmacokinet. 2010;49(4):239–58.
Kees F, Bucher M, Schweda F, Gschaidmeier H, Burhenne J, Mikus G, et al. Comparative bioavailability of the microemulsion formulation of cyclosporine (Neoral) with a generic dispersion formulation (Cicloral) in young healthy male volunteers. Ther Drug Monit. 2006;28(3):312–20.
Choi JG, Eom SM, Kim J, Kim SH, Huh E, Kim H, et al. A comprehensive review of recent studies on herb–drug interaction: a focus on pharmacodynamic interaction. J Altern Complement Med. 2016;22(4):262–79.
Robinson M, Zhang X. The world medicines situation report. WHO/EMP/MIE/2.3. Traditional medicines: global situation, issues and challenges. Geneva: World Health Organization; 2011.
Lau C, Mooiman KD, Maas-Bakker RF, Beijnen JH, Schellens JHM, Meijerman I. Effect of Chinese herbs on CYP3A4 activity and expression in vitro. J Ethnopharmacol. 2013;149(2):543–9.
Ashour ML, Youssef FS, Gad HA, Wink M. Inhibition of cytochrome P450 (CYP3A4) activity by extracts from 57 plants used in traditional Chinese medicine (TCM). Pharmacogn Mag. 2017;13(50):300–8.
Lee SS, Zhang B, He ML, et al. Screening of active ingredients of herbal medicine for interaction with CYP450 3A4. Phytother Res. 2010;21(11):1096–9.
Li Y, Ning J, Wang Y, Wang C, Sun C, Huo X, et al. Drug interaction study of flavonoids toward CYP3A4 and their quantitative structure activity relationship (QSAR) analysis for predicting potential effects. Toxicol Lett. 2018;294:27–36.
Xin HW, Wu XC, Li Q, et al. Effects of Schisandra sphenanthera extract on the pharmacokinetics of midazolam in healthy volunteers. Br J Clin Pharmacol. 2009;67(5):541–546.29.
Yingli G, Yanliu L, Ming Y, Haiyan S, Ping L, Guang J. Decade research progress and development trend of complex prescription compatibility of traditional Chinese medicine. World Sci Technol. 2012;14(3):1609–14.
Wu JJ, Ai CZ, Liu Y, Zhang YY, Jiang M, Fan XR, et al. Interactions between phytochemicals from traditional Chinese medicines and human cytochrome P450 enzymes. Curr Drug Metab. 2012;13(5):599–614.
Adiwidjaja J, Boddy AV, McLachlan AJ. Physiologically based pharmacokinetic modelling of hyperforin to predict drug interactions with St John’s wort. Clin Pharmacokinet. 2019:1–16.
Jamei M, Marciniak S, Edwards D, Wragg K, Feng K, Barnett A, et al. The Simcyp population based simulator: architecture, implementation, and quality assurance. In Silico Pharmacol. 2013;1(1):9.
Qi F, Zhu L, Li N, Ge T, Xu G, Liao S. Influence of different proton pump inhibitors on the pharmacokinetics of voriconazole. Int J Antimicrob Agents. 2017;49(4):403–9.
Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci. 2002;91(5):1358–70.
Brantley SJ, Gufford BT, Dua R, et al. Physiologically based pharmacokinetic modeling framework for quantitative prediction of an herb–drug interaction. CPT Pharmacometrics Syst Pharmacol. 2014;3(3):1–9.
Marsousi N, Desmeules JA, Rudaz S, Daali Y. Prediction of drug–drug interactions using physiologically-based pharmacokinetic models of CYP450 modulators included in Simcyp software. Biopharm Drug Dispos. 2018;39(1):3–17.
Li N, Zhu L, Qi F, Li M, Xu G, Ge T. Prediction of the effect of voriconazole on the pharmacokinetics of non-steroidal anti-inflammatory drugs. J Chemother. 2018;30(4):240–6.
Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transpl. 2008;22(1):1–15.
Schultz KR, Nevill TJ, Balshaw RF, Toze CL, Corr T, Currie CJ, et al. Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation. Bone Marrow Transplant. 2000;26(5):545–51.
Xue XP, Qin XL, Xu C, Zhong GP, Wang Y, Huang M, et al. Effect of Wuzhi tablet (Schisandra sphenanthera extract ) on the pharmacokinetics of cyclosporin A in rats. Phytother Res. 2013;27(8):1255–9.
Akool ES. Molecular mechanisms of the protective role of wheat germ oil against cyclosporin A-induced hepatotoxicity in rats. Pharm Biol. 2015;53(9):1311–7.
Rezzani R. Exploring cyclosporine A-side effects and the protective role-played by antioxidants: the morphological and immunohistochemical studies. Histol Histopathol. 2006;21(1/3):301.
Zeng H, Li D, Qin X, Chen P, Tan H, Zeng X, et al. Hepatoprotective effects of Schisandra sphenanthera extract against lithocholic acid-induced cholestasis in male mice are associated with activation of the pregnane X receptor pathway and promotion of liver regeneration. Drug Metab Dispos. 2016;44(3):337–42.
Loo WTY, Cheung MNB, Chow LWC. Fructus schisandrae (Wuweizi)-containing compound inhibits secretion of HBsAg and HBeAg in hepatocellular carcinoma cell line. Biomed Pharmacother. 2007;61(9):606–10.
Khadir F, Pouramir M, Joorsaraee SG, Feizi F, Sorkhi H, Yousefi F. The effect of arbutin on lipid peroxidation and antioxidant capacity in the serum of cyclosporine-treated rats. Caspian J Intern Med. 2015;6(4):196–200.
Madgula VLM, Avula B, Choi YW, Pullela SV, Khan IA, Walker LA, et al. Transport of Schisandra chinensis extract and its biologically-active constituents across Caco-2 cell monolayers—an in-vitro model of intestinal transport. J Pharm Pharmacol. 2008;60(3):363–70.
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Fan, J., Chen, L., Lu, X. et al. The Pharmacokinetic Prediction of Cyclosporin A after Coadministration with Wuzhi Capsule. AAPS PharmSciTech 20, 247 (2019). https://doi.org/10.1208/s12249-019-1444-6
- cyclosporin A
- Wuzhi capsule
- herb–drug interactions