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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

General Research Article

Absorption, Metabolism and Excretion of Surufatinib in Rats and Humans

Author(s): Ke Li, Sheng Ma, Liyan Miao*, Songhua Fan, Bin Pan, Weihan Zhang, Weiguo Su, Yating Xiong, Zheming Gu, Lian Guo and Yang Sai*

Volume 21 , Issue 5 , 2020

Page: [357 - 367] Pages: 11

DOI: 10.2174/1389200221666200514131721

Price: $65

Sekisui-XenoTech-CDM
Abstract

Background: Surufatinib is a potent small-molecule tyrosine kinase inhibitor and exhibited significant efficacy in the treatment of neuroendocrine tumors in clinical trials.

Objective: The absorption, metabolism and excretion of surufatinib were investigated in rats and human volunteers following a single oral dose of [14C] surufatinib.

Methods: The radioactivity was measured in plasma, urine, feces and bile by liquid scintillation counting, and the metabolites were characterized by liquid chromatography coupled to mass spectrometry.

Results: Surufatinib was orally absorbed similarly in rats and human volunteers, with the median Tmax of 4 hours post-dose. The estimated t1/2 appeared longer in humans than in rats (mean t1/2: 3.12 hour for male rats, 6.48 hours for female rats and 23.3 hours for male human volunteers). The excretion of surufatinib was almost complete in rats and human volunteers in the studies, with the total radioactivity recovery of >90% of the dose. Similarly, in rats and humans, fecal excretion predominated (approximately 87% of the dose recovered in feces and only 5% in urine). The parent drug was the major radioactive component detected in the plasma extracts of rats and humans, and no single circulating metabolite accounted for >10% of the total radioactivity. Unchanged drug was a minor radioactive component in the excreta of rats and humans.

Conclusion: Fecal excretion was the predominant way for the elimination of surufatinib and its metabolites in rats and humans. No disproportionate circulating metabolite was observed in humans.

Keywords: Anticancer drug, pharmacokinetics, absorption, excretion, metabolism, surufatinib.

Graphical Abstract
[1]
Dasari, A.; Shen, C.; Halperin, D.; Zhao, B.; Zhou, S.; Xu, Y.; Shih, T.; Yao, J.C. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol., 2017, 3(10), 1335-1342.
[http://dx.doi.org/10.1001/jamaoncol.2017.0589] [PMID: 28448665]
[2]
Fan, J.H.; Zhang, Y.Q.; Shi, S.S.; Chen, Y.J.; Yuan, X.H.; Jiang, L.M.; Wang, S.M.; Ma, L.; He, Y.T.; Feng, C.Y.; Sun, X.B.; Liu, Q.; Deloso, K.; Chi, Y.; Qiao, Y.L. A nation-wide retrospective epidemiological study of gastroenteropancreatic neuroendocrine neoplasms in china. Oncotarget, 2017, 8(42), 71699-71708.
[http://dx.doi.org/10.18632/oncotarget.17599] [PMID: 29069739]
[3]
Pavel, M.; O’Toole, D.; Costa, F.; Capdevila, J.; Gross, D.; Kianmanesh, R.; Krenning, E.; Knigge, U.; Salazar, R.; Pape, U.F.; Öberg, K. Vienna Consensus Conference participants. Vienna Consensus Conference participants. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology, 2016, 103(2), 172-185.
[http://dx.doi.org/10.1159/000443167] [PMID: 26731013]
[4]
Phan, A.T.; Halperin, D.M.; Chan, J.A.; Fogelman, D.R.; Hess, K.R.; Malinowski, P.; Regan, E.; Ng, C.S.; Yao, J.C.; Kulke, M.H. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol., 2015, 16(6), 695-703.
[http://dx.doi.org/10.1016/S1470-2045(15)70136-1] [PMID: 25956795]
[5]
Raymond, E.; Dahan, L.; Raoul, J.L.; Bang, Y.J.; Borbath, I.; Lombard-Bohas, C.; Valle, J.; Metrakos, P.; Smith, D.; Vinik, A.; Chen, J.S.; Hörsch, D.; Hammel, P.; Wiedenmann, B.; Van Cutsem, E.; Patyna, S.; Lu, D.R.; Blanckmeister, C.; Chao, R.; Ruszniewski, P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med., 2011, 364(6), 501-513.
[http://dx.doi.org/10.1056/NEJMoa1003825] [PMID: 21306237]
[6]
Kulke, M.H.; Lenz, H.J.; Meropol, N.J.; Posey, J.; Ryan, D.P.; Picus, J.; Bergsland, E.; Stuart, K.; Tye, L.; Huang, X.; Li, J.Z.; Baum, C.M.; Fuchs, C.S. Activity of sunitinib in patients with advanced neuroendocrine tumors. J. Clin. Oncol., 2008, 26(20), 3403-3410.
[http://dx.doi.org/10.1200/JCO.2007.15.9020] [PMID: 18612155]
[7]
Tran, T.A.; Leong, H.S.; Pavia-Jimenez, A.; Fedyshyn, S.; Yang, J.; Kucejova, B.; Sivanand, S.; Spence, P.; Xie, X.J.; Peña-Llopis, S.; Power, N.; Brugarolas, J. Fibroblast growth factor receptor-dependent and -independent paracrine signaling by sunitinib-resistant renal cell carcinoma. Mol. Cell. Biol., 2016, 36(13), 1836-1855.
[http://dx.doi.org/10.1128/MCB.00189-16] [PMID: 27141054]
[8]
Ries, C.H.; Cannarile, M.A.; Hoves, S.; Benz, J.; Wartha, K.; Runza, V.; Rey-Giraud, F.; Pradel, L.P.; Feuerhake, F.; Klaman, I.; Jones, T.; Jucknischke, U.; Scheiblich, S.; Kaluza, K.; Gorr, I.H.; Walz, A.; Abiraj, K.; Cassier, P.A.; Sica, A.; Gomez-Roca, C.; de Visser, K.E.; Italiano, A.; Le Tourneau, C.; Delord, J.P.; Levitsky, H.; Blay, J.Y.; Rüttinger, D. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell, 2014, 25(6), 846-859.
[http://dx.doi.org/10.1016/j.ccr.2014.05.016] [PMID: 24898549]
[9]
Xu, J.M.; Wang, Y.; Chen, Y.L.; Jia, R.; Li, J.; Gong, J.F.; Li, J.; Qi, C.; Hua, Y.; Tan, C.R.; Wang, J.; Li, K.; Sai, Y.; Zhou, F.; Ren, Y.X.; Qing, W.G.; Jia, H.; Su, W.G.; Shen, L. Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: results from a phase I study. Oncotarget, 2017, 8(26), 42076-42086.
[http://dx.doi.org/10.18632/oncotarget.14942] [PMID: 28159938]
[10]
Xu, J.; Li, J.; Bai, C.; Xu, N.; Zhou, Z.; Li, Z.; Zhou, C.; Jia, R.; Lu, M.; Cheng, Y.; Mao, C.; Wang, W.; Cheng, K.; Su, C.; Hua, Y.; Qi, C.; Li, J.; Wang, W.; Li, K.; Sun, Q.; Ren, Y.; Su, W. Surufatinib in advanced well-differentiated neuroendocrine tumors: a multicenter, single-arm, open-label, phase Ib/II trial. Clin. Cancer Res., 2019, 25(12), 3486-3494.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2994] [PMID: 30833272]
[11]
U. S. Food and Drug Administration/Center for Drug Evaluation and Research. Guidance for industry: safety testing of drug metabolites. FDA: Silver Spring 2020. Available at:. https://www.fda.gov/media/72279/download
[12]
U. S. Food and Drug Administration/Center for Drug Evaluation and Research, Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. FDA: Rockville 2003. Available at:. https://www.fda.gov/media/71311/download
[13]
U. S. Food and Drug Administration/Center for Drug Evaluation and Research, Guidance for industry: clinical drug interaction studies - cytochrome P450 enzyme- and transporter-mediated drug interactions. FDA: Silver Spring 2020. Available at:. https://www.fda.gov/media/134581/download
[14]
Hop, C.E.; Wang, Z.; Chen, Q.; Kwei, G. Plasma-pooling methods to increase throughput for in vivo pharmacokinetic screening. J. Pharm. Sci., 1998, 87(7), 901-903.
[http://dx.doi.org/10.1021/js970486q] [PMID: 9649361]
[15]
Van Vleet, T.R.; Liu, H.; Lee, A.; Blomme, E.A.G. Acyl glucuronide metabolites: Implications for drug safety assessment. Toxicol. Lett., 2017, 272, 1-7.
[http://dx.doi.org/10.1016/j.toxlet.2017.03.003] [PMID: 28286018]
[16]
Biernat, K.A.; Pellock, S.J.; Bhatt, A.P.; Bivins, M.M.; Walton, W.G.; Tran, B.N.T.; Wei, L.; Snider, M.C.; Cesmat, A.P.; Tripathy, A.; Erie, D.A.; Redinbo, M.R. Structure, function, and inhibition of drug reactivating human gut microbial β-glucuronidases. Sci. Rep., 2019, 9(1), 825-839.
[http://dx.doi.org/10.1038/s41598-018-36069-w] [PMID: 30696850]
[17]
Collins, S.L.; Patterson, A.D. The gut microbiome: an orchestrator of xenobiotic metabolism. Acta Pharm. Sin. B, 2020, 10(1), 19-32.
[http://dx.doi.org/10.1016/j.apsb.2019.12.001] [PMID: 31998605]

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