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.