Amr Ahmed EL-Arabey

Mohnad Abdalla

Wafa Ali Eltayb

Advanced Pharmaceutical Bulletin

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Adv Pharm Bull, 2019, 9(1), 1-4doi: 10.15171/apb.2019.001https://apb.tbzmed.ac.irMetformin: Ongoing Journey with Superdrug RevolutionAmr Ahmed EL-Arabey1* ID , Mohnad Abdalla2, Wafa Ali Eltayb31Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Egypt.2Qingdao Institute of Bioenergy and Bioprocess Technology, Qingdao Shi, Shandong Sheng 266000, People’s Republic of China.3Faculty of Science and Technology, Shendi University, Shendi, Nher Anile, Sudan.Dear Editor,Metformin a synthetic derivative of guanidine which isolated from the extracts of Galega officinalis in 1922 and introduced as a medication in France, England, Canada and the United States in (1957, 1957, 1972 and 1995, respectively). Metformin is a safe, essential, inexpensive medication with a story of more than 60 years. Indeed, metformin represents a worldwide superstar in therapy of patients with type 2 diabetes since its discovery.1 In last decade, several studies highlighted the beneficial therapeutic effects of metformin on other clinical domains such as cancer, aging, neurological diseases, cardio-vascular diseases, metabolic syndrome, Obesity and polycystic ovary syndrome. Moreover, the study conducted from 2009 to 2013 showed the off-label use of metformin among adolescents in United State approximately 6.5% diagnosed with obesity. However, further work on metformin actions for obesity could change its status to on label use by the FDA.2 Recent emerging evidence indicates novel actions of metformin in treatment of autoimmune disease through targeting signal transducer and activator of transcription 3 (STAT3) which responsible for macrophage polarization and reduced macrophage cytokines synthesis via inhibition of activating transcription factor 3 (ATF-3).3 Furthermore, the pioneer work by Piskovatska et al showed the therapeutic efficiency of metformin as a geroprotector through activation of autophagy and AMP-activated protein kinase (AMPK). In this respect, metformin act as a powerful candidate for hormesis inducing factor with pro-longevity features and health span enhancing.3,4 Clinically, metformin undergoing clinical trial for longevity phase 4 (NCT02432287) (clinicaltrial.gov). Moreover, metformin can be used as cytoprotective agent via reduction of apoptosis and oxidative stress.5 Hence, metformin act as super-drug against multiple diseases in numerous organs. Every cell has a membrane that separates the cell from the external environment, for this reason, handling of drugs mediated by a variety of different transport proteins. In this regards, transporters influences human *Corresponding Author: Amr Ahmed EL-Arabey, Email: amrel_arabey@azhar.edu.eg© 2019 The Author (s). This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.Letter to EditorReceived: 4 July 2018, Revised: 16 Dec. 2018, Accepted: 20 Dec. 2018, epublished: 21 Feb. 2019Figure 1. The OCT1, OCT2 and OCT3 expressions in human organs (http://www.proteinatlas.org). physiology and pathophysiology and are critical key players of therapeutic response for drugs.6 Furthermore, a number of important human drug transporters have been noted that are distributed at the apical or basal part of the epithelial cells in several tissues to orchestrate absorption, distribution and metabolism as well as drugs excretion. Importantly, membrane transporters play a considerable role in metformin absorption, distribution, and renal excretion. Multiple organic cation transporters (OCT1, OCT2 and OCT3) are determinants of the pharmacokinetics of metformin, and many of them are important in its pharmacological action, as mediators of metformin entry into target tissues.7,8 The OCT1, OCT2 and OCT3 are distributed in several human organs (Figure 1) . Here we would like to shed light on metformin EL-Arabey et alAdvanced Pharmaceutical Bulletin, 2019, Volume 9, Issue 12revolution in the current decade based on the completed and ongoing register clinical trials of metformin at (clinicaltrial.gov) (Table 1). Our analysis concerns the total clinical study of target organ of metformin according to the distribution of OCT1, OCT2 and OCT3 in human tissues. Interestingly, there are 541 completed and ongoing clinical trials of metformin on 26 target organs. However, there are no clinical trials of metformin on 11 potential target organs which can be reached by metformin such as appendix, tonsil, spleen, nasopharynx, bronchus, oral mucosa, salivary gland, small intestine, placenta, testis and soft tissue. Diverse scenarios have been manifested to illustrate the pharmacological mechanisms of metformin on different diseases for instance its metabolic effect, growth inhibition, partial inhibition of respiratory chain complex I, cell death, liver kinase B1 (LKB1)-dependent activation of AMPK, downstream of mammalian target of rapamycin (mTOR), autophagy effect, immune and hypothalamic effects.7 Consequently, research in needing to explore the therapeutic beneficial mechanisms of metformin in the uncovered promising target organs to draw the real picture for the ongoing revolution journey of metformin as super star drug.Table 1. Recorded clinical trials for metforminOrganTotal of studyStart time ConditionsStudy has resultsTransporterBrain 34 August 2001Brain tumor treated with cranial, cranial-spinal radiation, brain neoplasms, brain cancer, primary brain tumors, mild cognitive impairment, amnestic mild cognitive impairment, movement disorders, glioblastoma multiforme, Li-Fraumeni syndrome, Alzheimer's disease, vascular dementia, dementia, memory impairment, schizophrenia, depression, migraine.7OCT1 (cerebral cortex), OCT2 (cerebral cortex, hippocampus, Caudate, Cerebellum) and OCT3 (cerebral cortex, hippocampus, Caudate, Cerebellum)Thyroid gland and parathyroid gland3 April 2010Malignant neoplasm of thyroid stage I & II, thyroid hormone metabolism in euthyroid patients, mitigating side effects of radioactive iodine treatment in patients with differentiated thyroid cancer.-OCT1 (thyroid gland, parathyroid gland), and OCT3 (thyroid gland, parathyroid gland)Adrenal gland1December 2016Hyperandrogenemia - OCT1 and OCT3Appendix - - - - OCT3Tonsil - - - - OCT3Bone marrow 1 July 2013Adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with del(5q), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myelomonocytic leukemia (M4), adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b) blastic phase chronic myelogenous leukemia, recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia.- OCT1 and OCT3Lymph node 2 March 2008Lymphoma, metastatic melanoma (stage IIIC non-resectable or no surgically curable or stage IV).- OCT3Spleen - - - - OCT3Heart Muscle 12 May 2000Heart Failure, left ventricular hypertrophy, coronary artery disease, ischemic heart disease, peripheral arterial disease, intermittent claudication, fibromyalgia mitochondrial diseases, movement disorders.1 OCT1, OCT3Skeletal Muscle11 May 2000Physical inactivity and insulin resistance in skeletal muscle, studies in skeletal muscle in case of insulin sensitivity on reproductive function in polycystic ovary syndrome, muscle energetics, and vascular function in older adults with peripheral artery disease, muscle mitochondrial dysfunction in diabetes, defective atypical protein kinase C activation in diabetes and metabolic syndrome.1 OCT1, OCT3Nasopharynx - - - - OCT1, OCT3Metformin: Ongoing journey with Superdrug RevolutionAdvanced Pharmaceutical Bulletin, 2019, Volume 9, Issue 1 3Bronchus - - - - OCT1, OCT3Lung 14 March 2008Lung Cancer, lung neoplasms, idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, scleroderma associated pulmonary arterial hypertension, NSCLC, EGFR gene amplification, advanced cancer stage IIIB NSCLC, stage IV NSCLC, adenosquamous lung carcinoma, bronchioloalveolar carcinoma, large cell lung carcinoma, lung adenocarcinoma non-small cell lung carcinoma, recurrent non-small cell lung carcinoma, squamous cell lung carcinoma, stage IIIA & IIIB Non-small cell lung cancer, chronic obstructive pulmonary disease.1 OCT1, OCT3Liver 92October 2000Fatty liver, liver diseases, non-alcoholic fatty liver disease, liver cirrhosis, hepatic encephalopathy, hepatocellular carcinoma, hepatitis c, chronic cirrhosis, NASH related cirrhosis, hepatitis, steatohepatitis, abnormal liver function tests, intrahepatic cholestases, hepatic steatosis, acute liver injury.9 OCT1, OCT2, OCT3Gallbladder 2 July 2012Gallbladder emptying on postprandial glucagon-like peptide-1(GLP-1) secretion in type 2 diabetes.- OCT1, OCT3Pancreas 64 May 2000Stage IA, IB, IIA and IIB pancreatic adenocarcinoma, resectable pancreatic ductal adenocarcinoma, pancreatic cancer, acinar cell adenocarcinoma of the pancreas, recurrent pancreatic cancer, stage I-III pancreatic cancer, locally advanced pancreatic cancer, metastatic pancreatic cancer, unresectable pancreatic carcinoma, partial pancreatectomy resulting from benign pancreatic neoplasm.11 OCT1, OCT3Duodenum 3October 2012Metabolic effects of duodenal jejunal bypass plus sleeve gastrectomy in T2DM, familial adenomatous polyposis, morbidly obese adolescent with a duodena-jejunal liner.0 OCT1, OCT3Oral mucosa - - - - OCT3Colon and rectum15 March 2011Advanced colorectal cancer, recurrence of non-DM stage III colorectal cancer, refractory colorectal cancer, colorectal neoplasms, adenocarcinoma, metastatic colorectal cancer, adenomatous polyp, colorectal cancer, familial adenomatous polyposis, colon cancer, tertiary prevention in colon cancer.2 OCT1, OCT3Salivary gland - - - - OCT1, OCT3Esophagus 2 May 2010Short segment Barrett's esophagus, long segment Barrett's esophagus, esophageal cancer.1 OCT1, OCT3Stomach 1September 2009Gastric bypass - OCT1, OCT3Small intestine- - - - OCT1, OCT3Kidney 50September 1999Polycystic kidney, autosomal dominant, chronic kidney disease, renal insufficiency, chronic renal insufficiency, renal and vascular changes in type 2 diabetes, genetic basis for variation in the metformin renal elimination, reduced renal function, systemic and renal endothelial function, acute kidney injury, kidney cancer, kidney transplantation, chronic kidney disease, diabetic nephropathy, congenital nephrogenic diabetes insipidus. - OCT1, OCT2, OCT3Urinary bladder1October 2015Bladder cancer -Prostate 26 June 2009Prostate cancer, prostate cancer recurrent, prostatic neoplasms, metastatic prostate cancer, adenocarcinoma of the prostate, stage I, IIA, IIB & III prostate cancer.2 OCT3Testis - - - - OCT3Placenta - - - - OCT3Breast 38 October 2008Breast cancer, metastatic breast cancer, hormone receptor positive malignant neoplasm of breast, stage 0 breast carcinoma, breast neoplasms, stage I breast carcinoma, stage II breast carcinoma, stage III breast carcinoma,HER-2 positive breast cancer, locally advanced malignant neoplasm, human epidermal growth factor 2 negative carcinoma of breast, atypical ductal breast hyperplasia, BRCA1 & BRCA2 mutation carrier, ductal breast carcinoma in situ, lobular breast carcinoma in situ.1 OCT3Vagina 1January 2013Vaginal administration of metformin in Polycystic ovary syndrome patients.- OCT3Cervix,Uterine1 May 2015Uterine cervical neoplasms, squamous cell carcinoma, adenocarcinoma, carcinoma, aden-squamous.- OCT1, OCT3OrganTotal of studyStart time ConditionsStudy has resultsTransporterTable 1. ContinuedEL-Arabey et alAdvanced Pharmaceutical Bulletin, 2019, Volume 9, Issue 14Endometrium 8September 2010Adenocarcinoma of the endometrium, endometrial cancer, complex endometrial hyperplasia with atypia, grade 1 endometrial endometrioid adenocarcinoma.- OCT3Fallopian tube3October 2011Fallopian tube cancer, stage IIIA fallopian tube cancer, stage IIIB, IIIC & IV fallopian tube cancer, recurrent fallopian tube cancer.- OCT1, OCT3Ovary 124January 2000 Polycystic ovary syndrome, anovulation, infertility, endothelial dysfunction, reproductive endocrinology, hyperandrogenism, in vitro fertilization, recurrent miscarriage.4 OCT1, OCT3Adipose tissue26 May 2000Chronic inflammatory activation in fat tissue, obesity, metabolic syndrome, childhood obesity, lipodystrophy, liver fat content and visceral fat mass in overweight and obese type 2 diabetes patients, non-alcoholic fatty liver disease, pre-diabetes mellitus and obesity, HIV lipodystrophy.7 OCT3Soft tissue - - - - OCT3Skin 6February 2009Aging, psoriasis, acanthosis nigricans, psoriatic arthritis, chronic foot ulcers.1 OCT1, OCT2, OCT3Source: https://clinicaltrials.gov.OrganTotal of studyStart time ConditionsStudy has resultsTransporterTable 1. ContinuedEthical IssuesNot applicable.Conflict of Interest There is no conflict of interest to declare.References1. El-Arabey AA.  New insight for metformin against bladder cancer. Genes Environ  2017; 39:13. doi: 10.1186/s41021-017-0074-z2. El-Arabey AA. Update on off label use of metformin for obesity. Prim  Care Diabetes 2018;12(3):284-5. doi: 10.1016/j.pcd.2018.02.0043. Ursini  F,  Russo  E,   Pellino  G,   D’Angelo  S,   Chiaravalloti A,   De  SG,   et al. Metformin and Autoimmunity: A “New Deal” of an Old Drug. Front Immunol. 2018;9:1236.  doi: 10.3389/fimmu.2018.012364. Piskovatska V,  Stefanyshyn  N,   Storey  KB,   Vaiserman AM, Lushchak  O. Metformin as a geroprotector: experimental and clinical evidence. Biogerontology. 2019;20(1):33-48. doi: 10.1007/s10522-018-9773-5. 5. Ghasemnejad-Berenji M,   Ghazi-Khansari M,   Yazdani I,   Nobakht M,   Abdollahi A,   Ghasemnejad-Berenji  H, et al.  Effect of metformin on germ cell-specific apoptosis, oxidative stress and epididymal sperm quality after testicular torsion/detorsion in rats. Andrologia. 2018;50(2). doi: 10.1111/and.12846.6. Ciarimboli G. Role of organic cation transporters in drug-induced toxicity. Expert  Opin  Drug Metab Toxicol 2011;7(2):159-74. doi: 10.1517/17425255.2011.547474.7. Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J  Pharm  Sci  2017;106(9):2245-50. doi: 10.1016/j.xphs.2017.04.078.8. Pakkir Maideen  MM,   Jumale  A,   Balasubramaniam  R. Drug interactions of metformin involving drug transporter proteins. Adv  Pharm Bull.  2017;7(4):501-5. doi: 10.15171/apb.2017.062.

Metformin: Ongoing Journey with Superdrug Revolution

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