Wuzhi capsule regulates chloroacetaldehyde pharmacokinetics behaviour and alleviates high-dose cyclophosphamide-induced nephrotoxicity and neurotoxicity in rats
Li Chen
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXiaojuan Xiong
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXingyun Hou
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorHua Wei
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorJianxiu Zhai
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, China
Search for more papers by this authorTianyi Xia
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorXiaobin Gong
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorShouhong Gao
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorGe Feng
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXia Tao
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorCorresponding Author
Feng Zhang
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Correspondence
Feng Zhang and Wansheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Emails: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Wansheng Chen
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Correspondence
Feng Zhang and Wansheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Emails: [email protected] and [email protected]
Search for more papers by this authorLi Chen
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXiaojuan Xiong
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXingyun Hou
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorHua Wei
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorJianxiu Zhai
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
School of Traditional Chinese Material, Shenyang Pharmaceutical University, Shenyang, China
Search for more papers by this authorTianyi Xia
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorXiaobin Gong
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorShouhong Gao
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorGe Feng
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Key Laboratory of Jiangxi Province for Research on Active Ingredients in Natural Medicines, Bioengineering Research Institute, Yichun University, Yichun, China
Search for more papers by this authorXia Tao
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Search for more papers by this authorCorresponding Author
Feng Zhang
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Correspondence
Feng Zhang and Wansheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Emails: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Wansheng Chen
Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
Correspondence
Feng Zhang and Wansheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Emails: [email protected] and [email protected]
Search for more papers by this authorFunding information
This work was supported by National Science Foundation of China grants [Grant 81573793]; Shanghai Key Specialty Project of Clinical Pharmacy [Grant 2016-40044-002]; Important Weak Subject Construction Project of Shanghai Health Science Education [Grant 2016ZB0303]; and Beijing Medical Award Foundation [Grant YJHYXKYJJ-122]; Important Weak Subject Construction Project of Shanghai Health Science Education (2016ZB0303).
Abstract
High-dose cyclophosphamide (HD-CTX) treatment often leads to severe nephrotoxicity and neurotoxicity, which are mainly caused by one of its metabolites, chloroacetaldehyde (CAA). However, there are no effective antidotes to prevent these side effects. The objective of this study was to evaluate the effect of Wuzhi Capsule (WZC) on the pharmacokinetics of CTX and its metabolites in rats, and the attenuation of CAA induced kidney and brain injuries, which was produced at equimolar with 2-dechloroethylcyclophosphamide. Rats were treated with single- or multiple-dose of WZC when giving HD-CTX, and the plasma concentration of CTX and its metabolites were quantitated by UHPLC-MS/MS Single-dose, not multiple-dose of WZC co-administration (300 mg/kg) significantly reduced Cmax and AUC0→24 h of DC-CTX by 33.10% and 35.51%, respectively. Biochemical assay suggested oxidative stress was involved in kidney and brain injuries by HD-CTX, which were attenuated by single-dose WZC (300 mg/kg) pre-treatment, with increased glutathione, glutathione peroxidase and superoxide dismutase contents/or activities in both tissues and plasma (P < 0.05). Meanwhile, WZC pre-treatment could also significantly decrease the plasma levels of creatinine, blood urea nitrogen and malondialdehyde (P < 0.05). Additionally, WZC treatment improved the morphology and pathology condition of the kidneys and brains in rats. In conclusion, single-dose WZC co-administration decreased CAA production and exerted protective effect on CTX-induced oxidative stress in kidney and brain, whereas repetitive WZC co-administration with CTX was probably not recommended.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
Supporting Information
| Filename | Description |
|---|---|
| bcpt13211-sup-0001-Supinfo.docxapplication/docx, 210.8 KB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Brock N. Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture. Cancer Res. 1989; 49: 142-7.
- 2Ghosh D, Bose A, Haque E, Baral R. Pretreatment with neem (Azadirachta indica) leaf preparation in Swiss mice diminishes leukopenia and enhances the antitumor activity of cyclophosphamide. Phytother Res. 2006; 20: 814-818.
- 3Servais H, Ortiz A, Devuyst O, Denamur S, Tulkens PM, Mingeot-Leclercq MP. Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation. Apoptosis 2008; 13: 11-32.
- 4Rafiul HM, Ansari SH, Rashikh A. Coffea arabica seed extract stimulate the cellular immune function and cyclophosphamide-induced immunosuppression in mice. Iran J Pharm Res. 2013; 12: 101-108.
- 5Singh M, Kumar N, Shuaib M, Garg VK, Sharma A. A review on renal protective agents for cyclophosphamide induced nephrotoxicity. World J Pharm Pharmaceut Sci. 2014; 3: 737-747.
- 6Faussner F, Dempke WC. Multiple myeloma: myeloablative therapy with autologous stem cell support versus chemotherapy: a meta-analysis. Anticancer Res. 2012; 32: 2103-2109.
- 7Feng L, Huang Q, Huang Z, et al. Optimized animal model of CTX-induced bone marrow suppression. Basic Clin Pharmacol Toxicol. 2016; 119: 428.
- 8De Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet. 2005; 44: 1135-1164.
- 9Zhang J, Tian Q, Zhou S-F. Clinical pharmacology of cyclophosphamide and ifosfamide. Current Drug Therapy. 2006; 1: 55-84.
- 10Pohl J, Stekar J, Hilgard P. Chloroacetaldehyde and its contribution to urotoxicity during treatment with cyclophosphamide or ifosfamide. An experimental study/short communication. Arzneimittelforschung. 1989; 39: 704-705.
- 11Rzeski W, Pruskil S, Macke A, et al. Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol. 2004; 56: 351-360.
- 12Sood C, O'Brien PJ. 2-Chloroacetaldehyde-induced cerebral glutathione depletion and neurotoxicity. Br J Cancer Suppl. 1996; 27: S287-S293.
- 13Pourahmad J, Hosseini MJ, Eskandari MR, Rahmani F. Involvement of four different intracellular sites in chloroacetaldehyde- induced oxidative stress cytotoxicity. Iran J Pharm Res. 2012; 11: 265-276.
- 14Yu LJ, Drewes P, Gustafsson K, Brain EG, Hecht JE, Waxman DJ. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity. J Pharmacol Exp Ther. 1999; 288: 928-937.
- 15Huang Z, Roy P, Waxman DJ. Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochem Pharmacol. 2000; 59: 961-972.
- 16Wei H, Tao X, Di P, et al. Effects of traditional chinese medicine Wuzhi capsule on pharmacokinetics of tacrolimus in rats. Drug Metab Dispos. 2013; 41: 1398-1403.
- 17 Chinese Pharmacopoeia Commission. Pharmacopoeia of the People’s Republic of China, The first division of 2015 edition. Beijing, China: Chemical and Technologic Press. 2015: 215-216.
- 18Kim SR, Lee MK, Koo KA, et al. Dibenzocyclooctadiene lignans from Schisandra chinensis protect primary cultures of rat cortical cells from glutamate-induced toxicity. J Neurosci Res. 2004; 76: 397-405.
- 19Chiu PY, Leung HY, Siu AH, Poon MK, Ko KM. Schisandrin B decreases the sensitivity of mitochondria to calcium ion-induced permeability transition and protects against carbon tetrachloride toxicity in mouse livers. Biol Pharm Bull. 2007; 30: 1108-1112.
- 20Leong PK, Chiu PY, Chen N, Leung H, Ko KM. Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes. Free Radic Res. 2011; 45: 483-495.
- 21Jiang Y, Fan X, Wang Y, et al. Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration. Toxicol Sci. 2015; 143: 107-115.
- 22Jin J, Li M, Zhao Z, et al. Protective effect of Wuzhi tablet (Schisandra sphenanthera extract) against cisplatin-induced nephrotoxicity via Nrf2-mediated defense response. Phytomedicine 2015; 22: 528-535.
- 23Qin Xl, Chen X, Wang Y, et al. In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus. Drug Metab Dispos. 2014; 42: 193-199.
- 24Qin X-L, Chen X, Zhong G-P, 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: 766-772.
- 25Chen L, Xiong XJ, Gao SH, et al. UHPLC-MS/MS in simultaneous determination of cyclophosphamide and its metabolites in rat plasma. Acad J Second Mil Med Univ. 2016; 37: 1063-1069.
- 26Tvedennyborg P, Bergmann TK, Lykkesfeldt J. Basic & clinical pharmacology & toxicology policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol. 2018; 123: 233-235.
- 27Hundemer M, Engelhardt M, Bruckner T, et al. Rescue stem cell mobilization with plerixafor economizes leukapheresis in patients with multiple myeloma. J Clin Apher. 2014; 29: 299-304.
- 28Jung SH, Yang DH, Ahn JS, Kim YK, Kim HJ, Lee JJ. Advanced lytic lesion is a poor mobilization factor in peripheral blood stem cell collection in patients with multiple myeloma. J Clin Apher. 2014; 29: 305-310.
- 29Chen Q, Wu YJ, Cheng NN, Li YL, Wang YM. Dual effects of extract of Schisandra chinensis Baill on rat hepatic CYP3A. Yao Xue Xue Bao. 2010; 45: 1194-1198.
- 30Wang B, Yang S, Hu J, Li Y. Multifaceted interaction of the traditional Chinese medicinal herb Schisandra chinensis with cytochrome P450-mediated drug metabolism in rats. J Ethnopharmacol. 2014; 155: 1473-1482.
- 31Zhao LJ, Shou-Ting FU, Zhang CL, et al. Effects of Wuzhi capsule on pharmacokinetics of indinavir. Bull Acad Military Med Sci. 2008; 32: 353-362.
- 32Wang K, Qu QS, Zhang YX, Miao SZ, Jiang X. Effects of Wuzhi capsule on blood concentration of tacrolimus after renal transplantation. J Biol Regul Homeost Agents. 2016; 30: 155-159.
- 33Zhang H, Bu F, Li L, 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. 2017; 122: 331-340.
- 34Alsanad SM, Howard RL, Williamson EM. An assessment of the impact of herb-drug combinations used by cancer patients. BMC Complement Altern Med. 2016; 16: 393.
- 35Jürgens H, Exner U, Kühl J, et al. High-dose ifosfamide with mesna uroprotection in Ewing's sarcoma. Cancer Chemother Pharmacol. 1989; 24(Suppl 1): S40.
- 36Vose JM, Reed EC, Pippert GC, et al. Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: a randomized trial. J Clin Oncol. 1993; 11: 1306-1310.
- 37MacAllister SL, Martin-Brisac N, Lau V, Yang K, O'Brien PJ. Acrolein and chloroacetaldehyde: an examination of the cell and cell-free biomarkers of toxicity. Chem Biol Interact. 2013; 202: 259-266.
- 38Knouzy B, Dubourg L, Baverel G, Michoudet C. Targets of chloroacetaldehyde-induced nephrotoxicity. Toxicol In Vitro. 2010; 24: 99-107.
- 39Lai L, Hao H, Wang Q, et al. Effects of short-term and long-term pretreatment of Schisandra lignans on regulating hepatic and intestinal CYP3A in rats. Drug Metab Dispos. 2009; 37: 2399-2407.
- 40Wei H. Pharmacokinetic study of traditional Chinese medicine Wuzhi capsule and its drug-drug interaction with tacrolimus, Second Military Medical University, Shanghai, 2010.
- 41Iwata 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: 1351-1358.
- 42Li WL, Xin HW, Yu AR, Wu XC. In vivo effect of Schisandrin B on cytochrome P450 enzyme activity. Phytomedicine 2013; 20: 760-765.
- 43Mu Y, Zhang J, Zhang S, et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J Pharmacol Exp Ther. 2006; 316: 1369-1377.
- 44Craker LE, Giblette J. Chinese medicinal herbs: opportunities for domestic production. Trends in new crops and new uses. 2002: 491-496.
- 45Hu D, Cao Y, He R, et al. Schizandrin, an antioxidant lignan from Schisandra chinensis, ameliorates Abeta1-42-induced memory impairment in mice. Oxid Med Cell Longev. 2012; 2012: 721721.
- 46Yan T, Shang L, Wang M, et al. Lignans from Schisandra chinensis ameliorate cognition deficits and attenuate brain oxidative damage induced by D-galactose in rats. Metab Brain Dis. 2016; 31: 653-661.
Citing Literature
