Changes of Transporters and Drug-metabolizing Enzymes in Nephrotic Syndrome

Author(s): Yaqian Dong, Linna Gong, Xianyuan Lu, Mingguang Ye, Yu Lin, Shuting Xie, Jiaxing Zhang, Fenghua Zhou, Lan Tang, Wei Zou*, Menghua Liu*

Journal Name: Current Drug Metabolism

Volume 21 , Issue 5 , 2020

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Abstract:

Background: Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear.

Objective: Our study was to investigate the changes in the expression of main enzymes and drug transporters distributed in Adriamycin nephropathy rat liver, kidney, and intestine.

Methods: An intravenous injection with a single dose of Adriamycin (6mg/kg) was made to establish Adriamycin nephropathy (AN) model and normal groups were injected with normal saline. Serum was collected for lipid metabolism, renal, and hepatic function measurement. The real-time PCR and western blot were applied to determine the mRNA and protein expression of drug enzymes and transporters.

Results: In the kidney, a greater expression of Mdr1, Mrp2, Mrp4 Oat2 and Oct2 mRNA was found in AN rats as compared with control rats. In the liver, the expression of Bcrp mRNA was more doubled or tripled than control groups and downregulation of Mdr1, Mrp2, Mrp4 and Bsep gene expression was found in AN rats. Besides, we observed a downward trend of Cyp1a2, Cyp3a4 and Cyp2c9 mRNA levels in AN groups. In the duodenum, the expression of Mdr1 and Mrp3 mRNA level was decreased, while Bcrp and Mrp2 mRNA were increased.

Conclusion: The changes in drug-metabolizing enzymes and transporters expression in AN rats were clarified, which may be beneficial for understanding the altered pharmacokinetics and pharmacodynamics of clinical drugs and reduce unexpected clinical findings for nephropathy patients.

Keywords: Nephrotic syndrome, adriamycin, drug interaction, drug disposition, transporters, metabolic enzymes.

[1]
Hull, R.P.; Goldsmith, D.J. Nephrotic syndrome in adults. BMJ, 2008, 336(7654), 1185-1189.
[http://dx.doi.org/10.1136/bmj.39576.709711.80] [PMID: 18497417]
[2]
Kaysen, G.A. Nonrenal complications of the nephrotic syndrome. Annu. Rev. Med., 1994, 45, 201-210.
[http://dx.doi.org/10.1146/annurev.med.45.1.201] [PMID: 8198377]
[3]
Vaziri, N.D. Disorders of lipid metabolism in nephrotic syndrome: mechanisms and consequences. Kidney Int., 2016, 90(1), 41-52.
[http://dx.doi.org/10.1016/j.kint.2016.02.026] [PMID: 27165836]
[4]
Takeda, A.; Ohgushi, H.; Niimura, F.; Matsutani, H. Long-term effects of immunosuppressants in steroid-dependent nephrotic syndrome. Pediatr. Nephrol., 1998, 12(9), 746-750.
[http://dx.doi.org/10.1007/s004670050538] [PMID: 9874319]
[5]
Wu, K.C.; Lin, C.J. The regulation of drug-metabolizing enzymes and membrane transporters by inflammation: Evidences in inflammatory diseases and age-related disorders. Yao Wu Shi Pin Fen Xi, 2019, 27(1), 48-59.
[http://dx.doi.org/10.1016/j.jfda.2018.11.005] [PMID: 30648594]
[6]
Zha, W. Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases. Yao Wu Shi Pin Fen Xi, 2018, 26(2S), S32-S44.
[http://dx.doi.org/10.1016/j.jfda.2017.11.008] [PMID: 29703385]
[7]
Zanger, U.M.; Schwab, M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol. Ther., 2013, 138(1), 103-141.
[http://dx.doi.org/10.1016/j.pharmthera.2012.12.007] [PMID: 23333322]
[8]
Dong, Y.; van der Walt, N.; Pennington, K.A.; Yallampalli, C. Impact of adrenomedullin blockage on lipid metabolism in female mice exposed to high-fat diet. Endocrine, 2019, 65(2), 278-285.
[http://dx.doi.org/10.1007/s12020-019-01927-8] [PMID: 31025262]
[9]
Nigam, S.K. What do drug transporters really do? Nat. Rev. Drug Discov., 2015, 14(1), 29-44.
[http://dx.doi.org/10.1038/nrd4461] [PMID: 25475361]
[10]
Al-Ali, A.A.A.; Nielsen, R.B.; Steffansen, B.; Holm, R.; Nielsen, C.U. Nonionic surfactants modulate the transport activity of ATP-binding cassette (ABC) transporters and solute carriers (SLC): Relevance to oral drug absorption. Int. J. Pharm., 2019, 566, 410-433.
[http://dx.doi.org/10.1016/j.ijpharm.2019.05.033] [PMID: 31125713]
[11]
Liu, Y.; Pu, Q.H.; Wu, M.J.; Yu, C. Proteomic analysis for the impact of hypercholesterolemia on expressions of hepatic drug transporters and metabolizing enzymes. Xenobiotica, 2016, 46(10), 940-947.
[http://dx.doi.org/10.3109/00498254.2016.1144228] [PMID: 26887802]
[12]
Lu, T.; Zhu, X.; Xu, S.; Zhao, M.; Huang, X.; Wang, Z.; Zhao, L. Dosage optimization based on population pharmacokinetic analysis of tacrolimus in chinese patients with nephrotic syndrome. Pharm. Res., 2019, 36(3), 45.
[http://dx.doi.org/10.1007/s11095-019-2579-6] [PMID: 30719576]
[13]
Sun, J.Y.; Xu, Z.J.; Sun, F.; Guo, H.L.; Ding, X.S.; Chen, F.; Xu, J. Individualized tacrolimus therapy for pediatric nephrotic syndrome: considerations for ontogeny and pharmacogenetics of CYP3A. Curr. Pharm. Des., 2018, 24(24), 2765-2773.
[http://dx.doi.org/10.2174/1381612824666180829101836] [PMID: 30156148]
[14]
Wang, X.; Han, Y.; Chen, C.; Ma, L.; Xiao, H.; Zhou, Y.; Cui, Y.; Wang, F.; Su, B.; Yao, Y.; Ding, J. Population pharmacokinetics and dosage optimization of tacrolimus in pediatric patients with nephrotic syndrome
. Int. J. Clin. Pharmacol. Ther., 2019, 57(3), 125-134.
[http://dx.doi.org/10.5414/CP203355] [PMID: 30663980]
[15]
Tojo, A.; Hatakeyama, S.; Kinugasa, S.; Fukuda, S.; Sakai, T. Enhanced podocyte vesicle transport in the nephrotic rat. Med. Mol. Morphol., 2017, 50(2), 86-93.
[http://dx.doi.org/10.1007/s00795-016-0151-6] [PMID: 28314927]
[16]
Li, M.; Xu, M.; Liu, W.; Gao, X. Effect of CYP3 A4, CYP3 A5 and ABCB1 gene polymorphisms on the clinical efficacy of tacrolimus in the treatment of nephrotic syndrome. BMC Pharmacol. Toxicol., 2018, 19(1), 14.
[http://dx.doi.org/10.1186/s40360-018-0202-9] [PMID: 29615122]
[17]
Zhang, W.N.; Yang, L.; He, S.S.; Qin, X.M.; Li, A.P. Metabolomics coupled with integrative pharmacology reveal the protective effect of FangjiHuangqi Decoction against adriamycin-induced rat nephropathy model. J. Pharm. Biomed. Anal., 2019, 174, 525-533.
[http://dx.doi.org/10.1016/j.jpba.2019.05.023] [PMID: 31252309]
[18]
Bertani, T.; Poggi, A.; Pozzoni, R.; Delaini, F.; Sacchi, G.; Thoua, Y.; Mecca, G.; Remuzzi, G.; Donati, M.B. Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab. Invest., 1982, 46(1), 16-23.
[PMID: 6172662]
[19]
Mori, K.; Mukoyama, M.; Nakao, K. PPAR-α transcriptional activity is required to combat doxorubicin-induced podocyte injury in mice. Kidney Int., 2011, 79(12), 1274-1276.
[http://dx.doi.org/10.1038/ki.2011.36] [PMID: 21625258]
[20]
Cabeza, L.; Ortiz, R.; Prados, J.; Delgado, A.V.; Martín-Villena, M.J.; Clares, B.; Perazzoli, G.; Entrena, J.M.; Melguizo, C.; Arias, J.L. Improved antitumor activity and reduced toxicity of doxorubicin encapsulated in poly(ε-caprolactone) nanoparticles in lung and breast cancer treatment: An in vitro and in vivo study. Eur. J. Pharm. Sci., 2017, 102, 24-34.
[http://dx.doi.org/10.1016/j.ejps.2017.02.026] [PMID: 28219748]
[21]
Chang, S.Y.; Weber, E.J.; Ness, K.V.; Eaton, D.L.; Kelly, E.J. Liver and kidney on chips: microphysiological models to understand transporter function. Clin. Pharmacol. Ther., 2016, 100(5), 464-478.
[http://dx.doi.org/10.1002/cpt.436] [PMID: 27448090]
[22]
Hu, G.X.; Dai, D.P.; Wang, H.; Huang, X.X.; Zhou, X.Y.; Cai, J.; Chen, H.; Cai, J.P. Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population. Pharmacogenomics, 2017, 18(4), 369-379.
[http://dx.doi.org/10.2217/pgs-2016-0179] [PMID: 28244811]
[23]
Fan, H.Y.; Yang, M.Y.; Qi, D.; Zhang, Z.K.; Zhu, L.; Shang-Guan, X.X.; Liu, K.; Xu, H.; Che, X. Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats. Sci. Rep., 2015, 5, 12273.
[http://dx.doi.org/10.1038/srep12273] [PMID: 26194431]
[24]
Ivanyuk, A.; Livio, F.; Biollaz, J.; Buclin, T. renal drug transporters and drug interactions. Clin. Pharmacokinet., 2017, 56(8), 825-892.
[http://dx.doi.org/10.1007/s40262-017-0506-8] [PMID: 28210973]
[25]
Wen, S.; Wang, C.; Huo, X.; Meng, Q.; Liu, Z.; Yang, S.; Zhu, Y.; Sun, H.; Ma, X.; Liu, K. JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats. Toxicol. Lett., 2018, 295, 195-204.
[http://dx.doi.org/10.1016/j.toxlet.2018.06.1220] [PMID: 29964132]
[26]
Guo, X.; Meng, Q.; Liu, Q.; Wang, C.; Sun, H.; Peng, J.; Ma, X.; Kaku, T.; Liu, K. JBP485 improves gentamicin-induced acute renal failure by regulating the expression and function of Oat1 and Oat3 in rats. Toxicol. Appl. Pharmacol., 2013, 271(2), 285-295.
[http://dx.doi.org/10.1016/j.taap.2013.04.029] [PMID: 23707770]
[27]
Schneider, R.; Sauvant, C.; Betz, B.; Otremba, M.; Fischer, D.; Holzinger, H.; Wanner, C.; Galle, J.; Gekle, M. Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. Am. J. Physiol. Renal Physiol., 2007, 292(5), F1599-F1605.
[http://dx.doi.org/10.1152/ajprenal.00473.2006] [PMID: 17244891]
[28]
Lepist, E.I.; Zhang, X.; Hao, J.; Huang, J.; Kosaka, A.; Birkus, G.; Murray, B.P.; Bannister, R.; Cihlar, T.; Huang, Y.; Ray, A.S. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int., 2014, 86(2), 350-357.
[http://dx.doi.org/10.1038/ki.2014.66] [PMID: 24646860]
[29]
Smeets, P.H.; van Aubel, R.A.; Wouterse, A.C.; van den Heuvel, J.J.; Russel, F.G. Contribution of multidrug resistance protein 2 (MRP2/ABCC2) to the renal excretion of p-aminohippurate (PAH) and identification of MRP4 (ABCC4) as a novel PAH transporter. J. Am. Soc. Nephrol., 2004, 15(11), 2828-2835.
[http://dx.doi.org/10.1097/01.ASN.0000143473.64430.AC] [PMID: 15504935]
[30]
Bakos, E.; Evers, R.; Sinkó, E.; Váradi, A.; Borst, P.; Sarkadi, B. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol. Pharmacol., 2000, 57(4), 760-768.
[http://dx.doi.org/10.1124/mol.57.4.760] [PMID: 10727523]
[31]
El-Sheikh, A.A.; Masereeuw, R.; Russel, F.G. Mechanisms of renal anionic drug transport. Eur. J. Pharmacol., 2008, 585(2-3), 245-255.
[http://dx.doi.org/10.1016/j.ejphar.2008.02.085] [PMID: 18417112]
[32]
Lu, X.; Dong, Y.; Jian, Z.; Li, Q.; Gong, L.; Tang, L.; Zhou, X.; Liu, M. A systematic investigation of the effects of long-term administration of a high-fat diet on drug transporters in the mouse liver, kidney and intestine. Curr. Drug Metab., 2019, 20(9), 742-755.
[http://dx.doi.org/10.2174/1389200220666190902125435] [PMID: 31475894]
[33]
Jin, H.E.; Hong, S.S.; Choi, M.K.; Maeng, H.J.; Kim, D.D.; Chung, S.J.; Shim, C.K. Reduced antidiabetic effect of metformin and down-regulation of hepatic Oct1 in rats with ethynylestradiol-induced cholestasis. Pharm. Res., 2009, 26(3), 549-559.
[http://dx.doi.org/10.1007/s11095-008-9770-5] [PMID: 19002567]
[34]
Patel, M.; Taskar, K.S.; Zamek-Gliszczynski, M.J. Importance of hepatic transporters in clinical disposition of drugs and their metabolites. J. Clin. Pharmacol., 2016, 56(Suppl. 7), S23-S39.
[http://dx.doi.org/10.1002/jcph.671] [PMID: 27385177]
[35]
Thakkar, N.; Slizgi, J.R.; Brouwer, K.L.R. Effect of liver disease on hepatic transporter expression and function. J. Pharm. Sci., 2017, 106(9), 2282-2294.
[http://dx.doi.org/10.1016/j.xphs.2017.04.053] [PMID: 28465155]
[36]
Chen, L.; Manautou, J.E.; Rasmussen, T.P.; Zhong, X.B. Development of precision medicine approaches based on inter-individual variability of BCRP/ABCG2. Acta Pharm. Sin. B, 2019, 9(4), 659-674.
[http://dx.doi.org/10.1016/j.apsb.2019.01.007] [PMID: 31384528]
[37]
Ladda, M.A.; Goralski, K.B. The effects of CKD on cytochrome P450-mediated drug metabolism. Adv. Chronic Kidney Dis., 2016, 23(2), 67-75.
[http://dx.doi.org/10.1053/j.ackd.2015.10.002] [PMID: 26979145]
[38]
Yang, A.; Palmer, A.A.; de Wit, H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology (Berl.), 2010, 211(3), 245-257.
[http://dx.doi.org/10.1007/s00213-010-1900-1] [PMID: 20532872]
[39]
Müller, J.; Keiser, M.; Drozdzik, M.; Oswald, S. Expression, regulation and function of intestinal drug transporters: an update. Biol. Chem., 2017, 398(2), 175-192.
[http://dx.doi.org/10.1515/hsz-2016-0259] [PMID: 27611766]
[40]
Huang, S.M.; Temple, R.; Throckmorton, D.C.; Lesko, L.J. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin. Pharmacol. Ther., 2007, 81(2), 298-304.
[http://dx.doi.org/10.1038/sj.clpt.6100054] [PMID: 17259955]


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VOLUME: 21
ISSUE: 5
Year: 2020
Published on: 29 July, 2020
Page: [368 - 378]
Pages: 11
DOI: 10.2174/1389200221666200512113731
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