Metformin case

Diabetes is one of the most common worldwide diseases.

Almost 350 million people worldwide have diabetes. Diabetes
can increase the risk of other concomitant factors related to
the disease, such as obesity, cardiovascular disease, high
cholesterol, and hypertension. Diabetes and the incidences of
these factors cause an increase in the manifestation of renal
impairment and chronic kidney disease. Approximately one
of three adults with diabetes has renal impairment.
Metformin has been prescribed as type II diabetics first-line
treatment for more than 50 years (Rojas and Gomes 2013).
Metformin is an inexpensive drug and has many advantages
over other anti-diabetics drugs. This drug has an effect in
reducing the body weight and protecting against heart
disease, cancer, polycystic ovarian disease, and osteopenia
(Lalau 2010; Lalau et al. 2014). This drug also has fewer side
effects compared to all other oral anti-diabetic drugs (Lalau
2010; Asensio-López et al. 2011). The most serious side effect
of the drug is lactic acidosis. Though it is serious, lactic
acidosis induced by metformin is a rare side effect. Lactic
acidosis induced by metformin is observed in 9.7 events per
100,000 persons (Lalau 2010).

---OCT1 uptake transport is expressed mainly in basolateral

membrane of hepatocytes; OCT2 transporter is expressed highly in
the basolateral of renal tubular cells (Zolk 2011). The efflux
transporter MATE1 is expressed in several tissues such as skeletal
muscles, heart, and mainly concentrated in the apical tubular cells in
the kidney and hepatocytes in the liver. MATE2 efflux transporters
are highly distributed in tubular kidney cells (Fig. 1) (Hilgendorf
et al. 2007). However, the physiological parameters that describe the
reasons behind the drug accumulation in renal failure patients are
not fully understood. Because of the seriousness of this side effect in
these patients, very limited in vivo studies have been conducted.
--- Metformin is a biguanide, a strong base, and in typical gastric pHs
is protonated, bearing a positive charge. As a cationic, hydrophilic
drug, metformin is a substrate of various intestinal organic cation
transporters [11]. The ionized metformin has a tendency to stick to
the intestinal wall since the epithelium is negatively charged [12].
Data suggest that high concentrations of metformin are retained in
the upper parts of the GI tract for several hours, leading to depot-like
behavior [13–15]. The accumulation of metformin within the
intestinal wall could reduce the concentration gradient governing
passive absorption, overall decreasing bioavailability [16]. The low
absorption rate from the duodenum, jejunum, and ileum could
maintain high metformin concentrations in the small intestine [17].
The intestinal absorption is site-dependent and decreases along the
intestine (duodenum > jejunum > ileum) [18]. Moreover, metformin
has poor colonic absorption [12].
Metformin is not metabolized and is excreted unchanged in the urine.
At physiologic pH, it is hydrophilic due to the presence of a
quaternary ammonium group that results in a net positive charge.
Therefore, Metformin does not efficiently diffuse across the biological
membranes and requires carrier-mediated transport.

Multiple solute carrier transporters expressed in membranes of the

enterocytes, hepatocytes and the kidney are reported to be involved
in the absorption, distribution and elimination of metformin.
Metformin requires the entire length of the small intestine to be
absorbed (8): around 20% of the administered dose is absorbed in the
duodenum and 60% in the jejunum and ileum. The remainder
reaches the colon and remains unabsorbed. PMAT and OCT1 are
reported to play the major role in the intestinal absorption of
metformin (9). While PMAT is expressed in the apical (luminal)
membrane of the enterocytes, intestinal localization of OCT1 is
ambiguous (9-11). An association between reduced function alleles in
SLC22A1 and concomitant use of OCT1 inhibiting drugs with
metformin intolerance has been reported (12, 13). An interaction
between OCT1 and Serotonin Transporter (SERT) has also been
shown to play an important role in the pathophysiology of metformin
intolerance.
Metformin was reported as a substrate for the organic cation
transporters (OCTs), which are influx transporters starting with
OCT1, primarily found in the human liver, and OCT2 transporters
are located mainly in the kidney. Nonetheless, the OCT3 were not
inputted in the MH as they showed low affinity to MH and its
expression in the region of the human small intestine [20]. Also, the
multidrug and toxin extrusions (MATE1 and MATE2-K) efflux
transporters were the metformin substrate for them as the MATE1
expression is in the liver and kidney cells membrane. The kidney
cell’s membrane is the prominent place of MATE2-K [21]. In addition
and lately, Plasma Membrane Monoamine Transporter (PMAT)
identified affinity for MH uptake and expressed in the human small
intestine. All the km and Vmax values of the transporters.

Whilst PMAT shares extensive substrate and inhibitor overlap with

OCTs (14), there are no studies investigating its role in metformin
intolerance. Therefore, we hypothesized that reduced transport of
metformin by PMAT and/or OCT1 could increase intestinal
metformin concentration and subsequently increase the risk of GI
side effects. Definition of metformin intolerance The metformin
intolerance phenotype was defined in two ways: firstly, individuals
who switched to an alternative agent within 6 months of stopping
metformin (including modified release metformin) after having had
up to 1000 mg daily metformin for up to 6 weeks, who also reported
gastrointestinal side effects on the metformin treatment as the reason
for switching or where gastrointestinal side effects were clearly
documented in the clinical record as a reason for transfer. In an
alternative definition, intolerant individuals were defined as those
who could not increase their metformin immediate release dose above
500 mg daily despite an HbA1c > 7% (53 mmol/mol) and who either
reported gastrointestinal side effects on more than 500 mg, or where
gastrointestinal side effects were clearly documented in the clinical
record as a reason for transfer.

((Variation in the plasma membrane monoamine transporter

(PMAT, encoded in SLC29A4) and organic cation transporter 1
(OCT1, encoded in SLC22A1) and gastrointestinal intolerance to
metformin in type 2 diabetes: an IMI DIRECT study)).

The current evidence suggests that OCT1 is expressed in the human

intestine in small amounts (on gene and protein levels), while its
cellular localization in the apical or basolateral membrane of the
enterocytes remains to be finally defined, but functional data point to
a secretory function of the transporter at the basolateral membrane.
Thus, OCT1 should not be considered as a classical uptake
transporter in the intestine but rather as an intestinal elimination
pathway for cationic compounds from the systemic circulation.

The intestinal epithelium is by far more than a simple passive

diffusion barrier as assumed in earlier days. On the contrary,
enterocytes are equipped with many physiologically highly relevant
transporter proteins that mediate, on the one hand, a selective and
specific absorption of important nutrients and endogenous
compounds including peptides via the peptide transporter (PEPT)1
(SLC15A1), glucose via the sodium dependent glucose transporter 1
(SGLT1, SLC5A1), fatty acids via the monocarboxylate transporter
1 (MCT1, SLC16A1), cholesterol and phytosterols via ABCG5/G8,
bile acids via the apical sodium-dependent (ASBT, SLC10A1), and
vitamins via the sodium-dependent multivitamin transporter
(SMVT, SLC5A6)
On the other hand, intestinal transporters are recognized as
significant determinants of intestinal absorption of many drugs and
thus as important factors influencing their efficacy and safety
(Giacomini et al., 2010; Hillgren et al., 2013; Zamek-Gliszczynski et
al., 2018). In this regard, especially ATP-binding cassette (ABC)
transporters such as P-glycoprotein (P-gp, ABCB1), breast cancer
resistance protein (BCRP, ABCG2) and the multidrug resistance-
associated protein 2 (MRP2, ABCC2) have been extensively
investigated.

Differences in the longitudinal expression of ABC transporters along

the intestine, such as P-gp, were identified as the potential reason for
the phenomenon of regio-selective drug absorption (“absorption
window”), as observed when comparing different oral dosage forms
or by using intestinal perfusion catheter techniques.
EVIDENCE FROM EXPRESSION STUDIES
According to former studies on human OCT1, the transporter was
reported to be localized in the basolateral membrane of epithelial
cells in kidney, intestine as well as the liver (Jonker et al., 2001;
Jonker and Schinkel, 2004; Nies et al., 2009). Thus, it was assumed to
be involved in the intestinal excretion, hepatic uptake and renal
elimination of endogenous compounds and drugs, although more
recent studies have clearly demonstrated that OCT1 was not
expressed in the kidney (Prasad et al., 2016; Cheung et al., 2019;
Oswald et al., 2019).
In contrast to the well-established role of OCT1 in the hepatic
disposition of drugs, its role in the intestine remains still unclear. This
can be explained by the limited and in part controversial data on its
expression there. Several studies unambiguously demonstrated
mRNA expression of OCT1 in human intestinal tissue, although the
expression levels were much lower than that in the liver. More recent
mass spectrometry-based studies could also verify its protein
abundance. In each case, the protein abundance was low compared
to other important intestinal transporters such as P-gp or PEPT1.

There is no doubt that hepatic OCT1 can influence the

pharmacokinetics and in turn the efficacy and safety of several drugs
in a significant manner (Jonker and Schinkel, 2004; Koepsell et al.,
2007; Shu et al., 2007; Koepsell, 2015, 2020). In this regard, genetic
polymorphisms and DDIs were shown to result in drastically changed
serum levels of the respective substrates.

Accordingly, most bidirectional transport studies of OCT1 substrates

across Caco-2 cells demonstrated a markedly higher secretory
transport compared to the opposite direction (B-A > A-B), which
suggest a basolateral localization of OCT1.
As recently shown, OCT1 also contributes to thiamine uptake (Chen
et al., 2014). Here, Oct1 knockout in mice was associated with
dramatically reduced uptake of intravenously administered thiamine
into intestinal tissues confirming a basolateral localization of OCT1.
This assumption is also supported by several other former animal
experiments, in which direct excretion of intravenously administered
OCT1 substrates into the intestinal lumen was shown to be markedly
lower in Oct1- knockout mice.
Interestingly, OCT1 was also speculated to be involved in the efflux
of acylcarnitines from the liver to the systemic circulation (Kim et al.,
2017). Assuming OCT1 as a bidirectional transporter, it seems
possible that it may also be involved in drug absorption on the
basolateral membrane of the enterocytes. However, this hypothesis
needs to be proven by additional studies.