Generic placeholder image

Applied Clinical Research, Clinical Trials and Regulatory Affairs (Discontinued)

Editor-in-Chief

ISSN (Print): 2213-476X
ISSN (Online): 2213-4778

Review Article (Mini-Review)

Genotoxic Impurities in Ranitidine Containing Products: An Overview

Author(s): Shailesh Bhosale, Kamal Kant, Divya Goyal and Anoop Kumar*

Volume 7 , Issue 3 , 2020

Page: [155 - 161] Pages: 7

DOI: 10.2174/2213476X07666200423081738

Price: $65

Abstract

Ranitidine is a well known H2 blocker antihistaminic drug used for symptomatic relief of heartburn, indigestion, acid indigestion, peptic ulcer and hyperacidity. However, On 13th September 2019, the United States Food and Drug Administration (USFDA) has given an alerting statement regarding the presence of nitrosamine impurity called N-nitrosodimethylamine (NDMA) in ranitidine containing products. Recently, some pharmaceutical companies have also recalled their ranitidine containing products from the market. Thus, there is a need to understand about these impurities in ranitidine containing products. The first part of this article highlights the mechanism of action of ranitidine in established therapeutic indications along with its adverse drug reactions and contraindications. Further, the introduction of genotoxic impurities in pharmaceutical products along with its types and mechanism of toxicity of ranitidine containing genotoxic impurity have been discussed.

Keywords: Ranitidine, H2 blocker, genotoxic impurities, N-nitrosodimethylamine, pharmaceutical products.

Graphical Abstract
[1]
Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Ranitidine: a review of its pharmacology and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 1982; 24(4): 267-303.
[http://dx.doi.org/10.2165/00003495-198224040-00002] [PMID: 6128216]
[2]
Zeldis JB, Friedman LS, Isselbacher KJ. Ranitidine: a new H2-receptor antagonist. N Engl J Med 1983; 309(22): 1368-73.
[http://dx.doi.org/10.1056/NEJM198312013092206] [PMID: 6314139]
[3]
Carey PF, Martin LE, Owen PE. Determination of ranitidine and its metabolites in human urine by reversed-phase ion-pair high-performance liquid chromatography. J Chromatogr A 1981; 225(1): 161-8.
[http://dx.doi.org/10.1016/S0378-4347(00)80255-8] [PMID: 6271798]
[4]
Weingart J, Kunert H, Ottenjann R. Stimulation of gastric acid secretion by intravenous amino acid infusion and its inhibition by H2-receptor antagonists ranitidine and cimetidine. Br J Clin Pharmacol 1980; 10(2): 174-5.
[http://dx.doi.org/10.1111/j.1365-2125.1980.tb01739.x] [PMID: 6107119]
[5]
Pottegård A, Kristensen KB, Ernst MT, Johansen NB, Quartarolo P, Hallas J. Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study. bmj 2018; 362: k3851.
[http://dx.doi.org/10.1136/bmj.k3851]
[6]
Verna L, Whysner J, Williams GM. N-nitrosodiethylamine mechanistic data and risk assessment: bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacol Ther 1996; 71(1-2): 57-81.
[http://dx.doi.org/10.1016/0163-7258(96)00062-9] [PMID: 8910949]
[7]
Sobol Z, Engel ME, Rubitski E, Ku WW, Aubrecht J, Schiestl RH. Genotoxicity profiles of common alkyl halides and esters with alkylating activity. Mutat Res 2007; 633(2): 80-94.
[http://dx.doi.org/10.1016/j.mrgentox.2007.05.004] [PMID: 17644026]
[8]
Elder DP, Lipczynski AM, Teasdale A. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). J Pharm Biomed Anal 2008; 48(3): 497-507.
[http://dx.doi.org/10.1016/j.jpba.2008.06.009] [PMID: 18657926]
[9]
Bercu JP, Dobo KL, Gocke E, McGovern TJ. Overview of genotoxic impurities in pharmaceutical development. Int J Toxicol 2009; 28(6): 468-78.
[http://dx.doi.org/10.1177/1091581809349195] [PMID: 19966139]
[10]
Snodin DJ. Genotoxic impurities: from structural alerts to qualification. Org Process Res Dev 2010; 14(4): 960-76.
[http://dx.doi.org/10.1021/op100118e]
[11]
De Flora S, Zanacchi P, Camoirano A, Bennicelli C, Badolati GS. Genotoxic activity and potency of 135 compounds in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res 1984; 133(3): 161-98.
[http://dx.doi.org/10.1016/0165-1110(84)90016-2] [PMID: 6374443]
[12]
Elder DP, Snodin D, Teasdale A. Analytical approaches for the detection of epoxides and hydroperoxides in active pharmaceutical ingredients, drug products and herbals. J Pharm Biomed Anal 2010; 51(5): 1015-23.
[http://dx.doi.org/10.1016/j.jpba.2009.11.023] [PMID: 20031361]
[14]
Fan G, Tu Y, Chen C, Sun H, Wan C, Cai X. DNA methylation biomarkers for hepatocellular carcinoma. Cancer Cell Int 2018; 18(1): 140.
[http://dx.doi.org/10.1186/s12935-018-0629-5] [PMID: 30245591]
[15]
Zheng YF, Lu X, Zhang XY, Guan BG. The landscape of DNA methylation in hepatocellular carcinoma. J Cell Physiol 2019; 234(3): 2631-8.
[http://dx.doi.org/10.1002/jcp.27077] [PMID: 30145793]
[16]
Villanueva A, Portela A, Sayols S, et al. HEPTROMIC Consortium. DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma. Hepatology 2015; 61(6): 1945-56.
[http://dx.doi.org/10.1002/hep.27732] [PMID: 25645722]
[17]
George J, Tsuchishima M, Tsutsumi M. Molecular mechanisms in the pathogenesis of N-nitrosodimethylamine induced hepatic fibrosis. Cell Death Dis 2019; 10(1): 18.
[http://dx.doi.org/10.1038/s41419-018-1272-8] [PMID: 30622238]
[18]
Li P, He K, Li J, Liu Z, Gong J. The role of Kupffer cells in hepatic diseases. Mol Immunol 2017; 85: 222-9.
[http://dx.doi.org/10.1016/j.molimm.2017.02.018] [PMID: 28314211]
[19]
Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8(2): 108-18.
[http://dx.doi.org/10.1038/nrgastro.2010.213] [PMID: 21293511]
[20]
Liu H, Liao R, He K, Zhu X, Li P, Gong J. The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells. Immunol Lett 2017; 185: 79-83.
[http://dx.doi.org/10.1016/j.imlet.2017.02.016] [PMID: 28286228]
[21]
Wheeler MD. Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health 2003; 27(4): 300-6.
[PMID: 15540801]
[22]
Mekala S, Tulimilli SV, Geesala R, Manupati K, Dhoke NR, Das A. Cellular crosstalk mediated by platelet-derived growth factor BB and transforming growth factor β during hepatic injury activates hepatic stellate cells. Can J Physiol Pharmacol 2018; 96(8): 728-41.
[http://dx.doi.org/10.1139/cjpp-2017-0768] [PMID: 29558627]
[23]
Kiagiadaki F, Kampa M, Voumvouraki A, Castanas E, Kouroumalis E, Notas G. Activin-A causes Hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochim Biophys Acta Mol Basis Dis 2018; 1864(3): 891-9.
[http://dx.doi.org/10.1016/j.bbadis.2017.12.031] [PMID: 29287776]
[24]
Gressner AM. The cell biology of liver fibrogenesis - an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res 1998; 292(3): 447-52.
[http://dx.doi.org/10.1007/s004410051073] [PMID: 9582401]
[25]
Wang L, Tu L, Zhang J, Xu K, Qian W. Stellate cell activation and imbalanced expression of TGF-β1/TGF-β3 in acute autoimmune liver lesions induced by ConA in mice. BioMed Res Int 2017; 1-12.
[http://dx.doi.org/10.1155/2017/2540540]
[26]
Meng F, Wang K, Aoyama T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012; 143(3): 765-776.e3.
[http://dx.doi.org/10.1053/j.gastro.2012.05.049] [PMID: 22687286]
[27]
Holt AP, Salmon M, Buckley CD, Adams DH. Immune interactions in hepatic fibrosis. Clin Liver Dis 2008; 12(4): 861-82. x.
[http://dx.doi.org/10.1016/j.cld.2008.07.002] [PMID: 18984471]
[28]
Ruart M, Chavarria L, Campreciós G, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol 2019; 70(3): 458-69.
[http://dx.doi.org/10.1016/j.jhep.2018.10.015] [PMID: 30367898]
[29]
DeLeve LD. Liver sinusoidal endothelial cells and liver regeneration. J Clin Invest 2013; 123(5): 1861-6.
[http://dx.doi.org/10.1172/JCI66025]
[30]
Xie G, Choi SS, Syn WK, et al. Hedgehog signalling regulates liver sinusoidal endothelial cell capillarisation. Gut 2013; 62(2): 299-309.
[http://dx.doi.org/10.1136/gutjnl-2011-301494] [PMID: 22362915]
[31]
Burt AD. C. L. Oakley Lecture (1993). Cellular and molecular aspects of hepatic fibrosis. J Pathol 1993; 170(2): 105-14.
[http://dx.doi.org/10.1002/path.1711700203] [PMID: 8345406]
[32]
Zaldivar MM, Pauels K, von Hundelshausen P, et al. CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology 2010; 51(4): 1345-53.
[http://dx.doi.org/10.1002/hep.23435] [PMID: 20162727]
[33]
FDA updates and press announcements on NDMA in Zantac (ranitidine) 2020. Available from: http://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy