PHARMACOLOGICAL ASPECTS OF METFORMIN AND ITS ANALOGUES
Biguanides are anti-hyperglicemiant agents [5]. MET promotes reduction in hepatic glucose production, increased muscle uptake, decreased gastrointestinal absorption, in addition to being an insulin sensitizer [19]. The complex I of the electron transport chain was the first identified target of this drug, which acts as partial inhibitor of the mitochondrial complex [20-23]. The main effect of this inhibition is the activation of the AMPK and its pathways, which occurs through the stimulation of the regulatory subunit γ for the high levels of AMP/ADP [24,25].
The pharmacological aspects of MET were summarized in Chart 1. In a pharmacokinetic context, it differs from other biguanides by not suffering hepatic metabolism. The PMAT (plasma monoamine membrane transporter), located in the luminal side of the enterocytes, is one of the responsible for capturing the MET from the intestine. Moreover, the OCT transporters (organic cation carrier) have great importance in tissue distribution, particularly for MET. The OCT3 transporters deserve to be highlighted, because they are located in the brush border of the enterocytes and participate in the capture of the drug. The transport of MET and PHEN from the blood to the hepatocytes is mediated mainly by OCT1. On the other hand, the renal uptake of MET is mediated by OCT2 [27]. Urine excretion occurs via MATE1 and MATE2 (multidrug and toxin extrusion proteins transporters) [28]. The distribution volume of MET is 63 to 276L after an intravenous administration, while for a daily oral administration of 2g it is approximately 600L [27]. Its half-life with physiological renal function is approximately five hours [27,28], and the maximum recommended daily dose 2.55g [19].
PHEN and BUF present bioavailability of 40 to 50% after oral administration, accumulating mainly in the liver, pancreas, kidneys and muscles. Approximately 50% of PHEN is metabolized in the liver, which generates inactive metabolites. This way, the ”slow metabolizers” present a higher risk of developing lactic acidosis, the most important adverse effect of biguanides. PHEN is eliminated through urine and bile [5].
MET is a safe, well tolerated and accepted drug [19], since the adverse effects usually occur during the beginning of therapy and are resolved spontaneously [27]. Lactic acidosis occurs in five out of 100,000 individuals, generally being reported in patients with low tissue perfusion (e.g., sepsis, myocardial infarction and congestive heart failure) [27,28]. Renal insufficiency is the most common comorbidity present in patients with lactic acidosis associated with MET, being reported especially in those with high plasma creatinine levels (>3mg/dL) [28,30]. MET should not be used in moderate or severe renal insufficiency, or in those with mild but not stable renal failure [30]. Moreover, in severe cases of Sars-CoV-2 infection, there may be a need for drug interruption due to the presence of hypoxemia and hemodynamic instability, which increases the risk of lactic acidosis [31]. Adverse effects and contraindications have been listed in Chart 1.
The need for unconventional routes for the administration of biguanides is of great clinical importance, as it can direct the drug to the target organ/tissue and decrease possible systemic adverse effects. This is because the MET, after oral ingestion, is unable to be effectively distributed in the lungs [32]. Existing limitations trigger the need for different formulations and administration routes for biguanides. Drug administration systems (micro and nanoparticles, liposomes, niosomes, among others) are very useful to overcome the difficulties associated with conventional pharmaceutical forms. Among the potential advantages are the protection of the active against enzymatic degradation, reduction of side effects, reduction of the need for repetition of doses and alleviation of discomfort generated by the administration of the drug. Additionally, modulation of the release of the active principle(s) in the organism, control of the place where they are released, as well as an increase in the relative bioavailability of the drugs can be obtained [33].
Several studies point out the use of MET in unconventional ways, as in the topical use for the treatment of skin lesions or in the form of suppositories in patients with colorectal adenomas[34]. Experimental studies, in humans and animals, point MET as a promising agent in the treatment and prevention of lung diseases, but which end up having as a barrier the low concentration of the drug in the lungs[32]. Menendez, Quirantes-Piné and Rodríguez-Gallego et al. (2014), address the need for alternative formulations of biguanides related to the site where action is desired, such as inhalation use in lung cancer[35]. Berstein (2018) ratifies the administration of MET not only by oral route, highlighting the need to take into account its pharmacokinetics, in addition to its different serum and tissue concentrations when used by different routes[34]. In addition, inhibition of mitochondrial complex I by the drug may be useful to reduce oxidative stress and lung injury [36]. Thus, the use of inhaled biguanides to direct its actions may present great pharmacological potential, including for COVID-19.