Introduction
Diabetes mellitus was believed to be a kind of metabolic diseases due to
defects of insulin secretion, insulin action, or both, resulting in
hyperglycemia. It has also been believed that chronic hyperglycemia
caused by diabetes would do long-term harm to many organs such as eyes
and kidneys (Association, 2010). Diabetes would cause some serious
complications such as heart failure (Packer, 2021), diabetic nephropathy
(Donate-Correa et al., 2020) and diabetic foot (van Netten et al., 2020)
which not only do harm to the patients themselves but also cause large
burdens to social welfare.
A series of methods have been developed to treat this disease including
herb treatment, acupuncture, physical exercise, surgery and drug
treatment. Among them, drug treatment is the most widely used and
efficiency method in treating diabetes. There has already been a series
of drugs, including insulin stimulating agents which promote releasing
of insulin through interaction with specific receptor (Bruni et al.,
2021); Metformin type agents which have the ability to suppress hepatic
glucose production (Foretz et al., 2019); Thiazolidinediones type agents
which reduce insulin resistance via rising disposal insulin-dependent
glucose and reducing the production of hepatic glucose (Saltiel &
Olefsky, 1996); α-glucosidase inhibitors which could competitively
inhibit α-glucosidase and cause delayed glucose absorption in small
intestine (Hossain et al., 2020); Insulin, used in diabetes treatment
for decades, itself has the ability to regulate blood glucose (Mann et
al., 2020); Insulin analogues which modulate the ability of insulin to
control blood glucose level (Andersen et al., 2021) and incretins-based
hypoglycemic agents which stimulate insulin secretion from β cells (Chia
& Egan, 2020).
In classification of diabetes, one of the type is type 1 diabetes
mellitus (T1DM), characterized by destruction of insulin-producing cells
(Norris et al., 2020) while the other is type 2 diabetes mellitus
(T2DM), charactered by defective in insulin secretion and inability of
tissues responding to insulin properly (Galicia-Garcia et al., 2020). It
is also recognized that T1DM is influenced by immune while T2DM is
influenced by metabolic mechanisms (Eizirik et al., 2020). The
percentage of people suffering T2DM is much more larger than those with
T1DM (G. Xu et al., 2018) and treatment methods of T2DM is keeping on
booming.
In treating T2DM, incretins-based hypoglycemic agents were one of the
most up-to-date methods. Incretins are a kind of gut peptides which
could stimulate secretion of insulin combined with glucagon where GLP-1
(glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic
polypeptide) are two important incretin peptides (Nauck & Meier, 2018).
Based on these two peptides, the scientists have invented many
polypeptide compounds to mimic the function of these two peptides to
find treating methods for diabetes. However, these peptides could be
degraded at N-terminus by dipeptidylpeptidase-4 (DPP-4) rapidly. Thus,
DPP-4 could also be a potential target for treating diabetes. By
inhibiting this target, GLP-1 and its analogs could extend their
half-life resulting in longer time use in treating diabetes (Nangaku &
Wanner, 2021). This kind of agents could also treat some complications
such as diabetic nephropathy (Habib et al., 2021). Currently, two kinds
of drugs have already been approved by FDA and come to the market which
are GLP-1 receptor agonists (GLP-1 RA) and DPP-4 inhibitors.
The study of incretins-based hypoglycemic agents has attracted great
attention, however, the metabolism process of these kind of drugs still
lacking a comprehensive review to guide for metabolic process and drug
interactions. In this review, we summarize the characters and metabolism
processes of incretins-based hypoglycemic drugs. As long as our
knowledge, there has been no review based on metabolism and excretion of
GLP-1 RA and DPP-4 inhibitors. In writing this review, we hope it could
provide information and some instructions for clinical using these
drugs. It could also provide instructions for more comprehensive
research in the field of incretins-based hypoglycemic drugs metabolism.
Based on that, some modifications on these drugs could be carried out
for further treatment in T2DM.
Current incretins-based hypoglycemic agents
GLP-1 receptor agonists
GLP-1, an endogenous incretin hormone containing 30 amino acids, is
produced by enteroendocrine L-cells (Bae & Song, 2017). It could
decrease glycaemia via many pathways such as influencing secretion of
insulin, delaying empty of gastric, improving lipid metabolism as well
as promoting efficiency of pancreatic β-cell (Yaribeygi et al., 2020).
GLP-1 has become a therapeutic target in treating T2DM, which could be
activated by GLP-1 RAs to improve the tolerance of glucose and dwindle
the hazards of hypoglycemia. GLP-1 RAs might also have potential to
slowing the disease progression (Werner et al., 2010). Current GLP-1
receptor agonists approved are shown on Table 1.
Exenatide, also known as Byetta™ produced by Amylin/Eli Lilly, is an
incretin mimetic peptide and it is the first approved GLP-1 RA by FDA.
This drug is a synthetic form of naturally occurred exendin-4 (Nielsen
et al., 2004), having ability to regulate glucose level and be approved
as a drug in treating T2DM. Exenatide is reported to have similar
structure and function to human endogenous GLP-1 (Cvetković & Plosker,
2007), sharing 53% amino acid sequence same comparing with human GLP-1,
which is a partial analogue with human endogenous GLP-1. This drug is
not a substrate for DPP-4 for the amino acid difference at position 2
having an alanine substitute in GLP-1, making it longer half-life in
plasma (Barnett, 2007).
Liraglutide also known as Victoza®, invented by Novo
Nordisk, is a human GLP-1 analogue consisting 97% homology amino acid
comparing with human endogenous GLP-1. Only one amino acid was
substituted from lysine to arginine at position 34. In order to avoid
being degraded by DPP-4, it is modified by a fatty acid molecule binding
to albumin, making it half-life longer (Jackson et al., 2010).
Albiglutide, invented by GlaxoSmithKline, is a GLP-1 RA having distinct
chemical structure. It has two copies of modified human GLP-1, both
containing fragments from 7 to 36 with slight modification from alanine
to glycine. One copy’s C-terminal was fused with another’s N-terminal
whose C-terminal connected with human albumin (Rendell, 2016). The
substitution at position 8 makes it resist to DPP-4 which could make it
longer half-life and less frequent dosing (Trujillo & Nuffer, 2014).
Dulaglutide, known as Trulicity™ produced by Eli Lilly and Company, is a
fusion protein, consisting two identical chains linked by disulfide
bonds. On each of the chain, it contains a sequence like human GLP-1
which could covalently linked by a small peptide linker to modified
human IgG4 heavy chain fragment (Sanford, 2014). In GLP-1 analog part,
some of the amino acids were substituted comparing with human GLP-1 for
higher solubility, protecting itself from being degraded by DPP-4 to
optimize clinical profile. These modifications make the drug consists
about 90% homologous to human GLP-1 (Scheen, 2017).
Lixisenatide, developed by Sanofi‐Aventis, is a human GLP-1 receptor
agonist used for treatment of T2DM which has structure modified from
exendin-4 at C-terminal with six lysine residues. This drug has great
affinity to native human GLP-1 receptor. For the reason that it has a
modified structure, it could enhance its half-life in avoid of being
degraded by DPP-4 (Christensen et al., 2009; Werner et al., 2010).
Semaglutide, Ozempic® invented by Novo Nordisk, is
known as a GLP-1 RA. It has two substitutions comparing with human GLP-1
which were alanine to alpha-amino isobutyric acid at position 8 and
lysine to arginine at position 34. For the lysine at position 26, it was
acylated to get its derivates and made connection with glutamic acid
moiety combined with a C-18 fatty diacid side chain (Christou et al.,
2019; Lau et al., 2015). Semaglutide has long half-life, making it
possible to have only one subcutaneous administration per week. It is
also reported that this drug has better efficiency on controlling weight
and treating obesity (Christou et al., 2019).
Tirzepatide, invented by Eli Lilly and Company, is a dual GIP and GLP-1
receptor agonist in treating T2DM. Tirzepatide uploaded its New Drug
Application (NDA) recently to FDA. Signaling study in pharmacology
indicated that this drug has more affinity to GIP receptor, meaning that
it is more involved in GIP receptor rather than GLP-1 receptor (Thomas
et al., 2021; Willard et al., 2020). Tirzepatide is a linear peptide
whose structure modified from GIP, connected with a C20
fatty diacid moiety
linked to lysine at position 20 (Coskun et al., 2018; Frias et al.,
2020).
DPP-4 inhibitors
DPP-4 is a 110 kDa glycoprotein expressed on the surface of many cells,
which could cleave N-terminal dipeptides from incretin hormones. Thus,
DPP-4 is believed to be an important target for diabetes treating
(Röhrborn et al., 2015). By inhibiting this target, it could have the
potential for treating T2DM. Current DPP-4 inhibitors approved are shown
on Table 2.
Sitagliptin, also known as Januvia™, Glactiv® and
Tesavel® originally marketed by Merck and Company
(Stofella et al., 2019), is an oral DPP-4 inhibitor first launched and
approved by FDA. According to structure–activity relationship (SAR)
study, this structure has more opportunities to become a candidate
(Weber & Thornberry, 2007). Long term study showed that Sitagliptin
administration would not bring about additional safety concerns
(Yoshikawa et al., 2020).
Saxagliptin, known as Onglyza™ was first invented by AstraZeneca used
for treatment of T2DM by inhibiting DPP-4. This drug could also combine
other treatment method such as with metformin or insulin in T2DM with
mild or severe renal impairment (Yang, 2012). The chemical structure has
four chiral carbon atoms, making it possible for 8 stereoisomers (Dong
et al., 2014). According to SAR, tyrosine at position 662 and 470 may be
the key residue for DPP-4 inhibition.
Linagliptin, funded by Boehringer Ingelheim and Eli Lilly and Company,
having its name as Trajenta®, Tradjenta™, Trazenta™
and Trayenta™, act as a high selective oral active DPP-4 inhibitor whose
feature is a predominantly nonrenal elimination drug. The dosage form
contained linagliptin/metformin is known as
Jentadueto® (Deeks, 2012). Many synthetic route of
Linagliptin has been reported, many of the methods using 3-methyl
xanthine as starting material (Chavan et al., 2020). According to SAR
studies, it has two binding interactions with the target (Li et al.,
2021).
Alogliptin is a small molecule and orally active selective DPP-4
inhibitor funded by Takeda. Using structure-based design, it is
hypothesized that it should contain a quinazolinone scaffold and some
other chemical structures put in the other pocket to meet favorable
physical properties (Feng et al., 2007). SAR studies emphasized the
importance of this chemical structure comparing with other potential
structures (Parsa & Pal, 2011).
Vildagliptin, first invented by Novartis which also known as
Galvus®, Jalra® and
Xiliarx®, could not only act as DPP-4 inhibitor alone
in treating T2DM but could combine administrate with metformin. Some
dosage are pre-treated dosage, making metformin or vildagliptin treating
together with the compound, which are known as
Eucreas®, Icandra®,
Zomarist® (Keating, 2010). New formulation forms such
as making Vildagliptin connected to metal nanoparticles such as gold and
silver, dwindling IC50 to make DPP-4 inhibitory factor
better (Fayyaz et al., 2020).
Gemigliptin, Zemiglo®, was developed by LG Life
Sciences as a potent and selective DPP-4 inhibitor for treatment of T2DM
(Kim et al., 2013). The drug have totally different structure with other
DPP-4 inhibitors for it contains pyrimidine piperidine derivative (Gutch
et al., 2017). Combinational of this drug with insulin or other
anti-diabetes drug perform good efficiency and tolerance (Cho et al.,
2020).The efficiency and safety of this drug alone is also believed to
be well tolerated and with no extra risk of body weight influencing
(Yoon et al., 2017).
Teneligliptin has five consecutive rings forming a ‘J-shaped’ structure
DPP-4 inhibitor for treatment of T2DM (Goda & Kadowaki, 2013) invented
by Mitsubishi Tanabe Pharma Corporation (Kadowaki et al., 2018). The
efficiency and safety of long-term using this drug contains no extra
issues (Kadowaki et al., 2020). There have been some reports that
Teneligliptin has the potential to treat radiation-induced
cardiotoxicity by reducing expression of IL-1β and MCP-1, inhibiting
activation of NF-κB and improving ration of Bax/Bcl-2 (Peng et al.,
2020).
Omarigliptin also known as Marizev®, which is an
orally administrate DPP-4 inhibitor invented by Merck for treatment of
T2DM (Burness, 2015). In the process of developing this drug,
tetrahydropyran analogues Omarigliptin was selected as a candidate using
SAR (Biftu et al., 2014). This drug is generally well tolerated and
could help control blood glucose level clinically (Kadowaki et al.,
2021).
Metabolism and elimination of incretins-based hypoglycemic
agents
GLP-1 receptor agonists
3.1.1. Exenatide
In human, Exenatide was mainly degraded at kidney and has quiet
significant species difference. In human, the cleavage sites are at the
amino acid sequence between 21/22 and 22/23. Exenatide was further fully
completed degraded by kidney membranes and into peptides less than 3
amino acids. Those with liver impairment seem to not affect elimination
and degradation of Exenatide. Exenatide 1-22 and 23-39 cannot act as the
agonists or antagonists to Exenatide (Copley et al., 2006).
The concentration in plasma increased in a dose dependent manner. The
mean half-life of Exenatide ranging from 3.3 - 4 hours and median time
to peak (tmax) is approximately 2.2 hours (Kolterman et
al., 2005). For those who have renal impairment, Exenatide clearance
could be dwindled remarkably (Linnebjerg et al., 2007). New doses of
Exenatide have been invented which greatly improve its pharmacokinetic
performance (Cui et al., 2021).
Drug interactions correlate with Exenatide was generally gastric
emptying which was decided by Exenatide administration time. It is
reported that oral drugs depending on threshold concentrations should be
administered no less than 1 hour before using Exenatide in avoid of drug
interactions (Cvetković & Plosker, 2007). When combine Acetaminophen
use with Exenatide, there was no significant effect on Exenatide
pharmacokinetics (Bray, 2006).
3.1.2. Liraglutide
In metabolism of Liraglutide, the drug is cleaved by DPP-4 in the Ala 8
– Glu 9 position of the N-terminus and the product could be further
degraded by NEP into several metabolites. Chromatographic performance of
metabolized Liraglutide is similar to metabolized GLP-1. There is lower
than detection level amount of prototype Liraglutide could be detected
in urine and feces and low amount of prototype Liraglutide could be
detected in plasma, indicating that Liraglutide has been degraded
completely in body (Malm-Erjefält et al., 2010).
The mean half-life of the drug is reported to be 13.5 hours. There is no
significant difference in pharmacokinetics for gender and age. However,
the body weight was reported to have potential for influencing area
under the curve (AUC) which decrease with increasing body weight
(Damholt et al., 2006; Jacobsen et al., 2016). Within the range of 0.6 -
3 mg, it has been reported that the amount of exposure increased in a
dose dependent manner. The rate of clearance is about 0.9–1.4 L/h (Lin
et al., 2020).
For drug interactions, Liraglutide has small potential in reacting with
Cytochrome P450 (CYP450) enzymes as well as plasma protein binding.
However, this drug might cause drug interactions in other methods such
as influence gastric emptying, thus some orally administrated drugs
could be influenced such
as acetaminophen
(Bode, 2012). There are reports that combine use of Liraglutide with
insulin detemir would have no pharmacokinetic interaction (Morrow et
al., 2011).
3.1.3. Albiglutide
The metabolic process for Albiglutide is by urine ubiquitous proteolytic
enzymes in vascular endothelium (Davis et al., 2015). Albiglutide has
its molecular size for 73,000 Da and could be degraded into small
peptides and some single amino acids which could not be cleared in the
glomeruli in normal state (Rendell, 2018).
The absorption is predominantly via the lymphatic circulation. Age and
body weight was reported to have effects on clearance of Albiglutide
(Young et al., 2014). It has its half-life for approximately five days
and could maintain in a steady state after 4 - 5 days. Albiglutide could
be excreted through kidney, the body clearance is reported to be 67 mL/h
(Davis et al., 2015). For those have renal impairment, exposure of
Albiglutide increased 30% - 40% (Trujillo & Nuffer, 2014).
Albiglutide is reported to be safe in coadministration with Digoxin or
Warfarin at appropriate dose without needing of dosage adjustment (Bush
et al., 2012), thus it might be safe for treating T2DM patients who
still receiving treatment for cardiovascular diseases. However, this
drug has great influence on pharmacokinetics on Simvastatin, causing AUC
decreases 40%, however, maximum concentration (Cmax)
increased by 18% (Brønden et al., 2015).
3.1.4. Dulaglutide
It is estimated that Dulaglutide’s
excretion was like general protein catabolism pathways which be degraded
into small polypeptides. It is believed that Dulaglutide would not be
eliminated through glomerular filtration or CYP450 enzymes (Nauck,
2016).
There is no significant difference in Dulaglutide pharmacokinetics
between healthy volunteers and those with T2DM. It has a low absorption
rate which reaches its Cmax within the range of 24 - 72
hours, having its median in 48 hours. The steady plasma concentration
could maintain 2 - 4 weeks. The elimination half-life at 0.75 or 1.5 mg
doses is reported to be around 5 days. Those patients with renal or
liver failure either mild or severe showed no clinical change in some
pharmacokinetics data such as AUC and Cmax (Sanford,
2014).
Dulaglutide could cause delayed gastric emptying. It is also normal for
those patients with T2DM experience gastrointestinal disorders, thus the
drug interactions for orally administrated drugs should be investigated.
It is reported that Dulaglutide did not affect important pharmacokinetic
data of Digoxin, Warfarin and Atorvastatin if they are administrated
together (de la Peña et al., 2017). However, it is still need to pay
attention to of coadministration of rapid gastrointestinal absorption
drugs (Burness & Scott, 2015).
3.1.5. Lixisenatide
Lixisenatide acts as a polypeptide whose excretion method generally act
as endogenous peptides which could filtered by renal, reabsorption by
tubular and subsequent metabolic catabolism where CYP450 enzymes do not
participate in metabolizing of which. All the metabolites could be
detected are polypeptides degraded from Lixisenatide and the main
metabolites do not show any biological activities (Use, 2013).
The half-life of Lixisenatide was reported to be within the range of 2.7
- 4.3 hours. AUC and Cmax increased with the increasing
of dose and dose frequency where at the concentration of 20 μg has the
largest AUC (Barnett, 2011; Christensen et al., 2009). In those patients
with renal impairment, Lixisenatide is generally well tolerated and has
good efficiency (Leiter et al., 2014).
Lixisenatide would cause delayed gastric emptying which could cause
reduction for orally administered drugs in absorption rate. In normal
treatment with Ethinylestradiol, Levonorgestrel and Atorvastatin, there
is no need of adjusting dose (Elkinson & Keating, 2013).
3.1.6. Semaglutide
Most of the Semaglutide is circulated in plasma at a percentage of 83%
in human as primary component. It has both injection and oral given
dosage forms where the oral given dose is co-formulated with the
absorption enhancer (Granhall et al., 2019). The drug is metabolized
prior to excretion primarily in urine. Besides Semaglutide, a total of
six metabolites were identified in human plasma and the major of which
takes up to 7.7%. This metabolite was identified to contain His 7- Tyr
19 sequence. For all the metabolites, they are believed to form
proteolytic cleavage in the peptide backbone area and beta-oxidation of
the fatty acid side chain. 53% of the drug could be recovered in urine,
18.6% in feces while 3.2% in expired air. The parent drug together
with 21 metabolites could be detected in urine and no form of parent
drug could be detected in feces (Hall et al., 2018; Jensen et al.,
2017).
For oral given doses, whose median tmax was 1.5 hours
for a single dose (Bækdal et al., 2021) and the steady state achieved
after 4 - 5 weeks. The half-life is approximately 1 week and could keep
on circulation for about 5 weeks (Clements et al., 2021). After giving
multiple doses, the AUC ranges from 19.7% to 34.9% while the total
variability ranged between 63.6% and 84.4% (Granhall et al., 2019).
For the injection dose, Semaglutide could reach its Cmaxwithin the range of 24 - 56 hours. The bioavailability of Semaglutide is
reported to be 94%. For the metabolites, they are witnessed to decline
over time in plasma and only the parent drug could be detected over 28
days after administration (Hall et al., 2018). It seems that at least
part of Semaglutide is metabolized in liver, thus pharmacokinetics of
Semaglutide could be influenced for those patients with liver impairment
(Jensen et al., 2018). However, in the trial for those with renal
impairment, the pharmacokinetics of Semaglutide is not influenced by
renal impairment (Granhall et al., 2018).
For drug interactions appeared in Semaglutide, it has potential for
causing delay in gastric emptying. Semaglutide was reported to have
potential in increasing AUC of metformin, not increasing the half-life
of Lisinopril and Warfarin. It is also reported that Semaglutide would
not affect contraceptive drug Ethinylestradiol and Levonorgestrel’s
bioavailability (Hedrington & Davis, 2019).
3.1.7. Tirzepatide
In metabolizing Tirzepatide, it was primarily via catabolism of the
peptide backbone and β-oxidation of the di-acid chain. Since this drug
has just uploaded its application to FDA, there is still lacking of
researches on human. The parent drug is the main metabolites in
circulation, accounting to higher than 80% in both monkey and rats. The
drug is mainly excreted through urine and feces (Martin et al., 2020).
In healthy volunteers, Cmax is considered to be
dose-proportional within the range of 26- 874 ng/mL at the dosage
between 0.25 mg and 8.0 mg, while tmax occurred at the
range of 1- 2 days after administration. The half-life is 116.7 hours
which is almost 5 days (Frías, 2020). For those patients with renal
impairment, the pharmacokinetics is not influenced by renal function
(Urva et al., 2021).
This drug would also cause gastric emptying delay as other GLP-1
agonists (Urva et al., 2020). Since Tirzepatide has just been approved,
there has not been much data on drug interactions reported. However, in
comparing with other drugs, Tirzepatide is superior to titrated insulin
degludec (Ludvik et al., 2021) and metformin (FRIAS et al., 2021).
DPP-4 inhibitors
3.2.1. Sitagliptin
14C labeling Sitagliptin was applied for studying
absorption, metabolism and elimination in human. Majority of drug was
excreted through kidney and 87% of drugs could be recovered in urine,
while the other 13% was excreted through fecal. In metabolism process,
16% of drug was excreted in the form of metabolites where urines take
up 13% and feces take up 3%. The metabolites are N-sulfate derivates,
N-carbamoyl glucuronic acid derivates, a mixture of hydroxylated
derivatives, an ether glucuronide of a hydroxylated metabolite and two
metabolites formed by oxidative desaturation of the piperazine ring
followed by cyclization. Enzymes participate in the metabolism process
are major CYP3A4 while CYP2C8 also made minor contribution (Vincent et
al., 2007).
From 1.5 - 600 mg administration, plasma Sitagliptin increased almost
proportionally and the half-life was approximately 8 - 14 hours while
tmax values varied from 1 - 6 hours based on dosage.
Clearance of Sitagliptin in renal was about 388 mL/min (Herman et al.,
2005). For those who have liver injury, researchers recognized that
although statistics in pharmacokinetic showed slight increasing in
Cmax, however, this would not affect the drug use in
patients (Migoya et al., 2009).
In Sitagliptin, when combining the drug with grapefruit, which may
interact with many drugs’ metabolisms process, the drug come to systemic
circulation increased while there has not witnessed significant change
in the process of total elimination and residence time (FARES et al.,
2021). Drug interaction with Lobeglitazone, a drug used for treating
non-alcoholic fatty liver disease in T2DM (Lee et al., 2017) showed no
significant change in pharmacokinetics meaning that no dose adjustment
is needed when combination use of these two drugs (Moon et al., 2020).
Combination of Tinospora cordifolia aqueous extract which is
beneficial to diabetes as complementary treatment with Sitagliptin also
showed no significant change in pharmacokinetics (Vora et al., 2020).
3.2.2. Saxagliptin
After receiving treatment of Saxagliptin, the main component related was
the parent drug and in the form of 5-hydroxy Saxagliptin which is an
active metabolite. The other metabolites may come from hydroxylation at
other positions of the drug and conjugate the parent drug with
glucuronide or sulfate. In CYP450 enzymes, CYP3A4 and CYP3A5 played an
important role in forming metabolites where the kinetic of CYP3A4 is
much more higher than CYP3A5 (Su et al., 2012). Within 7 days, 97% of
the drug could be eliminated in the excreta where 74.9% in urine and
22.1% in feces. The major component in the excreta was in the form of
parent drug and 5-hydroxy Saxagliptin, having a percentage of 24.0% and
44.1% respectively.
The elimination process of Saxagliptin was mainly through renal and
hepatic routes. The half-lives of Saxagliptin and 5-hydroxy Saxagliptin
were reported to be 6.7 and 8.1 hours respectively (Boulton, 2017). For
those who have renal failure, attentions should be paid when taking this
drug. The AUC of Saxagliptin is correlated with renal impairment. For
those who have severe renal impairment, AUC of Saxagliptin and 5-hydroxy
saxagliptin was 108% and 347% higher than those with normal renal
function (Boulton et al., 2011).
For drug interactions, the combination use of Rifampicin would not
significantly influence Saxagliptin, thus it is unnecessary to adjust
the dosage of Saxagliptin when combining use (Upreti et al., 2011).
However, processed rhubarbs used for anti-diabetic would have some
effects on CYP450 enzymes, modifying the metabolism of Saxagliptin. As a
result, the dose of Saxagliptin should be adjusted when combined treated
with rhubarbs (Gao et al., 2013).
3.2.3. Linagliptin
Whichever the administration method of Linagliptin is orally or
intravenously, the dominant excretion pathway is through fecal at a
percentage of 84.7% and 58.2% respectively while those excreted
through renal took up for 5.4% and 30.8% respectively. Most of the
drugs maintained in its unchanged form while its metabolites
S-3-hydroxypiperidinly derivative of Linagliptin which forms through a
two-step mechanism containing larger than 10% of total drugs. The
formation of this metabolite is mediated by CYP3A4, aldo-keto reductases
and some carbonyl reductases (Blech et al., 2010).
Linagliptin has a good absorption after oral administration. After about
90 minutes of administration, Cmax would be reached and
after 4 days the concentration could be in a steady state. Linagliptin
is unique for it does not have a linear dose-proportional AUC and
Cmax which could be explained as whose two-compartmental
model could have higher affinity to the target (Graefe-Mody et al.,
2012).
When combinational use of Fimasartan which is used for treating
hypertension and heart failure, together with Linagliptin, it is
reported that there is no significant change in pharmacokinetics, thus
these two drugs could be used together (Kang et al., 2020). There are
also suggestions that Linagliptin could be used together with Digoxin,
which indicates that Linagliptin has no interactions with P-glycoprotein
(Friedrich et al., 2011). Although Linagliptin has the potential to
inhibit OCT1 and OCT2, however, its low therapeutic concentration in
plasma would hardly result in transporter-mediated drug-drug
interactions (Ishiguro et al., 2013).
3.2.4. Alogliptin
Alogliptin is primarily eliminated in urine in the form of parent drug
at a percentage of higher than 60%. CYP2D6 participates in metabolism
of Alogliptin. The metabolites are primarily N-demethylation metabolite
which is active, the product then get acetylation to acquire inactive
metabolite. In plasma and urine, the two metabolites make up less than
2% and 6% respectively. The renal clearance was within the range of
8.6 – 13.6 L/h (Scott, 2010).
Alogliptin has a good bioavailability which could be almost 100% while
tmax reached the peak 1-2 hours after administration.
Small intestine was the place where absorption primarily occurs. Food
intake was reported not to have much influence AUC, only
Cmax was slightly influenced but not significantly in
clinical. In patients with T2DM, the half-life of Alogliptin is 12.5 -
21.1 hours where administration of 25 mg which is the maximum
recommended dose reaching its half-life at about 21 hours (Dineen et
al., 2014). In addition, the experiments carried on animals also support
a once-daily dosing regimen (Lee et al., 2008).
In order to avoid drug interactions, some studies regarding combined use
of other drugs were applied. It was reported that Alogliptin combine
administration with metformin or cimetidine would not affect its
pharmacokinetics (Karim et al., 2010). The drug was mediated by some
transporters which are sensitive to fruit juice in intestine. This would
result in inhibiting intestinal adsorption of Alogliptin (Morimoto et
al., 2021).
3.2.5. Vildagliptin
Using 14C labeling Vildagliptin for determination of
absorption, metabolism and elimination in human. The major component in
plasma was in the form of parent drug and a carboxylic acid derivate
which account for 25.7% and 55% respectively. It was calculated that
85.4% of Vildagliptin could obtain in urine where 22.6% maintained in
the form of parent drug while the other was in feces where 4.54%
maintained in the form of parent drug. There are a total of four
metabolism pathways in Vildagliptin metabolism, the most important of
which was resulting from cyano group hydrolysis which not associated
with CYP450 enzymes (He et al., 2009).
In patients with T2DM, Vildagliptin could be absorbed rapidly, the
elimination half-life was reported to be 1.32 - 2.43 hours (He et al.,
2007). Within the range of 25 - 200 mg, half-life showed an increasing
in dose dependent manner from 1.6 - 2.5 hours (Hu et al., 2009). In
order to improve the pharmacokinetics statistics for its low half-life,
a controlled release dosage form was reported to be prepared, the dosage
contained Guar gum could keep the drug releasing up to 24 hours
(Balakrishnan et al., 2021).
CYP enzymes showed limited role in metabolizing Vildagliptin for it
usually metabolized through oxidative process. Thus, this drug usually
would not interact with other drugs commonly metabolized by CYP enzyme
systems (He, 2012).
3.2.6. Gemigliptin
Through the excretion of Gemigliptin, a total of 90.5% was recovered
over 192 hours where 63.4% comes from urine and 27.1% comes from
feces. A total of 23 metabolites were observed in plasma, where the
parent drug is the most abundant component, which takes up
44.8% - 67.2% in urine and 27.7% - 51.8% in fecal. For the other
compounds, the hydroxylated metabolite which was dominantly metabolized
by CYP3A4 was the second most abundant compound, making up to more than
10% (Kim et al., 2014).
After receiving 50mg Gemigliptin, the drug was absorbed very quickly,
reaching its Cmax for approximately 1.8 hours while AUC
increased proportionally with increasing of dosage administration and
the terminal half-life was 17.1 hours. It is also reported that it would
not accumulate and could combine administration with food or not (Kim et
al., 2016). For those who have renal impairment, both
Cmax and AUC increased based on their degree of renal
diseases, ranging from increasing 1.20 to 1.50. However, it is suggested
that the dosage of Gemigliptin administration do not need adjustment in
renal impairment patients (Shon et al., 2014).
When combine the drug with Ketoconazole or Rifampicin, the
pharmacokinetics changed significantly, suggesting that when combining
the use with drugs have CYP3A4 interaction activity, the dosage of
administration should change (Noh et al., 2012). When combine the drug
with Glimepiride, pharmacokinetic properties was not altered and the
dosage do not need change (Choi et al., 2014).
3.2.7. Teneligliptin
Larger than 90% of Teneligliptin could be excreted in 216 hours after
administration where 45.4% could be excreted in urine and 46.5% could
be excreted in feces. For the metabolites, the major component are the
parent drug and its thiazolidine-1-oxide derivative, which takes up for
14.85% and 17.7% respectively. In human, the most important enzymes
participate in metabolizing should be CYP3A4 and FMO3 (Nakamaru et al.,
2014).
After given different dose of Teneligliptin from 2.5 mg to 160 mg
orally, Cmax and AUC increased in a dose dependent
manner. The elimination half-life of Teneligliptin is 24.2 hours.
Teneligliptin might be a suitable drug for those patients with hepatic
and renal impairment for it has many elimination pathways where around
65.6% goes through metabolism and 34.4% goes through excretion
(Ceriello et al., 2019). For those who have renal impairment, reported
not to have influences on Cmax. In addition, dialysis
would not affect the safety of Teneligliptin (Halabi et al., 2013).
In combination use of Teneligliptin and Canagliflozin, there is no
strong pharmacokinetics interaction and could be administrated together
in treating T2DM (Kinoshita & Kondo, 2015). Other researches focused on
its interactions with SLGT2 inhibitor, current SLGT2 inhibitors were
reported to have small interactions with Teneligliptin in
pharmacokinetic study (Gu et al., 2020).
3.2.8. Omarigliptin
Omarigliptin absorbed very quickly. In excretion method, around 74.4%
of the drug was observed in urine and 3.4% was observed in feces. In
urine, the form of parent drug is the major component in urine,
indicating that renal excretion of the unchanged drug is most important.
There are no major metabolites could be detected in plasma (S. Xu et
al., 2018).
At different dosage, tmax value could range from 0.75 -
4.0 hours. Within the range of 0.5- 400mg, Cmax and AUC
almost in a dose dependent manner and within two days, the urinary
excretion data is 1.6 - 2.7 L/h. Tmax value under the
circumstance of fasted conditions is 1.5 hours while under fed
conditions were reported to be 4 hours (Krishna et al., 2016). For those
patients with renal impairment, due to pharmacokinetics reason, the dose
should be halved (Jain et al., 2019).
The risk of drug interactions in Omarigliptin is quiet low for it does
not inhibit CYP450 enzymes and some key drug transporters. In addition,
it does not have induction reaction to some important CYP450 enzymes
(Evans & Bain, 2016).
Discussion and Conclusion
There have already been a lot of approved drugs by FDA in GLP-1 receptor
agonists and DPP-4 inhibitors for treating T2DM and they have been
widely used and showed effective and available to patients (Aroda et
al., 2012). Thus, the metabolism and excretion study of these drugs are
of much significance and worthwhile thoroughly review.
For GLP-1 agonists (Fig. 1), they are generally polypeptides with
modifications of some amino acids. Sine majority of GLP-1 agonists mimic
endogenous polypeptide, the metabolism of them is major through
degradation into small polypeptides and amino acids by some enzymes,
quite different from chemical drugs. Some drugs are modified with some
chemical structures and these parts are usually metabolized by oxidation
process while the polypeptide parts are usually metabolized by
degradation. CYP450 enzymes played limited role in metabolizing these
drugs which are generally not the substrates of them (Evans et al.,
2009). This would relate to fewer interactions between GLP-1 agonists
and those drugs metabolized by CYP450 enzymes, making great potential
for treating those symptoms together with T2DM. In addition, since they
mimic the sequence of endogenous polypeptide with limited alteration or
modification, the degradation of them is inevitable by natural enzymes
which specifically degrade them, such as DPP-4, which would cause severe
influence on pharmacokinetic as well as bioavailability to these drugs.
Currently, some GLP-1 agonists with small molecular weight are being
developed, which make them avoid being degraded by some enzymes.
However, how these drugs could be metabolized and how they could have
interactions is still to be found. In addition, some new formulations
could be invented for combining treatment. This kind of drugs generally
has the potential for causing delayed gastric emptying (Quast et al.,
2020; Xie et al., 2021), which might have pharmacokinetics interaction
with those orally administered drugs in absorption rates. In addition,
some patients due to the limit of age and conditions of diseases might
have some basic drawbacks in their stomachs, thus, some extra studies
are still in need. Most of the metabolites could be found in urine and
some other components could be found in feces, air and plasma, meaning
that kidney is one of the key organs that participate in excretion of
these drugs. The patients with renal failure have the potential to have
difficulties in metabolizing these drugs, making some data regarding
pharmacokinetics larger than normal patients (Trujillo & Nuffer, 2014).
Since most of the drugs would result in delayed gastric emptying which
result in pain in patients, whether this drug could co-formulate with
some drugs such as Motilium to accelerate gastric emptying to avoid this
adverse effect (Mcfarlane et al., 2018). However, currently no report or
even clinical trials were reported to have in solving this adverse
effect. If this could be solved, some major drug interactions could be
handled, giving large potential for treating T2DM. Since T2DM might
relate to lacking of renal functions, thus the development of new
treating methods remedy for lacking of renal function’s excretion is of
great significance. In drug design, choosing the peptides chain the
drugs mimic, considering whether it could be degraded by some special
enzymes need great attentions. In order to optimize the
pharmacokinetics, some modifications could be added to the peptide chain
such as adding some functional groups or building disulfide bonds. In
addition, some of the sequence could be altered to optimize the
pharmacokinetics, such as change from natural existed amino acids to
unnatural amino acids. In addition, the pharmacokinetics should also be
carefully considered such as different half-life, how these drugs could
be applied in different conditions should also be a key consideration.
The metabolism and excretion process should give more considerations to
avoid damage to some organs especially stomach and kidney.
For metabolism of DDP-4 inhibitors (Fig. 2), most of the drugs are
metabolized by CYP450 enzymes where CYP3A4 played a major role and the
metabolites could be witnessed in excreta (Kalhotra et al., 2018). The
half-life of this kind of drugs is almost within a day while limited of
them could maintain their half-life over than three days. Some of drugs
listed majorly metabolized by cyano group hydrolysis enzyme and FMO3
rather than CYP450 enzymes (Nakamaru et al., 2014). Since most of the
drugs are substrates of CYP450 enzymes, combinational use of some drugs
metabolizing by CYP450 enzymes or even some grapefruits might result in
significant change in pharmacokinetics. In general, combinational use
drugs which do not have induction or inhibition ability to CYP450
enzymes are safer in pharmacokinetics. In addition, some efficiency and
safety studies of drug interactions should carry out before combing use
really be approved. In daily food ingestion and some complementary
treatment, some reports emphasized that daily intake food, fruit or
traditional medicine could also influence the metabolism and
pharmacokinetics of some DPP-4 inhibitors. For patients, before taking
some foods, it is important to seek for advice from doctors whether they
are appropriate for use (FARES et al., 2021). For excretion of the
metabolites, most of the compounds are in the form of its parent drug
via urine. The other main pathways of excretion are eliminated through
feces, which generally not as much as those excreted through urine.
Thus, whether those patients with renal impairment need to adjust the
dose of administration in a problem need to be studied (Boulton et al.,
2011). Some studies could still carry out to show the detailed
mechanisms of renal excretion of these metabolites. For the other data
related to pharmacokinetics, it may relate to dosage forms and chemical
structure to form a short-term or long-term dosage which could be used
for different types of treatment in meeting of different conditions. In
design of new drug candidate, some derivates of currently approved
compounds could be developed where some functional groups could be
altered or coupling with some macromolecules to optimize the data in
pharmacokinetics.
Comparing GLP-1 RAs and DPP-4 antagonists (Table 3), both of these kinds
of drugs have been approved by drug administration authorities and
proved to be useful in clinic in treating T2DM. GLP-1 RAs are generally
peptide kinds drugs that administrated through injection while DPP-4
antagonists are generally chemical compounds that administrated orally
or injection. In metabolizing these two kinds of drugs, CYP450 enzymes
participate in metabolizing majority of DPP-4 inhibitors while GLP-1 RAs
are often metabolized through peptide degradation. Comparing the
difference between these two drugs, the half-life for DPP-4 antagonists
is generally shorter which might result from they are exogenous and be
metabolized through a totally different metabolizing pathway comparing
with GLP-1 RAs. For different drug interactions, these two kinds of drug
are totally different, GLP-1 RAs in general would cause delayed gastric
emptying which might relate to late adsorption of some orally intake
drug but cause limited reactions with CYP450 enzymes while some DPP-4
inhibitors are substrates of CYP450 enzymes, either inhibitor or
inducer, making those drugs metabolized by CYP450 enzymes have potential
interactions with them. Based on differences in situation of
individuals, whether their liver, gastric or kidney be in good
condition, the two kinds of drugs could be applied differently. For
those who have gastric diseases, great attention should be paid in using
GLP-1 RAs while those have hepatitis diseases, using DPP-4 should be
paid more attentions. CYP enzymes and delayed gastric emptying would
also cause drug interactions. When treating symptoms together with T2DM,
the co-administration of drugs should carry out researches before
approved on clinical use on patients. Despite quite different chemical
structures, majority of these drugs are excreted through urine. Thus, it
is of great significance to investigate whether the patients with renal
impairment could withstand drugs of these kinds. In the process of new
drug development, some functional groups could be added or altered to
improve pharmacokinetic. In the field of peptides, the sequence could be
further consideration in order to avoid being degraded by enzymes in a
fast rate.
In this review, we hope the information provided could inspire those in
need. Based on the conditions of diseases or physical conditions, the
choice between GLP-1 RAs and DPP-4 antagonists are variable. In treating
of complications in T2DM, the selections of drugs in avoid of
interactions and make good supplementary. In satisfying different need
of lasting time, the choices of different chemical structures and dosage
forms could be applied. We also hope that based on the information and
ideas provided, some drugs with novel structures, could improve drug
interactions and friendly to renal failure patients could be invented in
the near future.
Herein, we reviewed the physiological disposition of two kinds currently
incretins-based hypoglycemic agents, which are GLP-1 RAs and DPP-4
antagonists for treating T2DM. Based on what we have reviewed in this
article, it is hopeful that this would provide how the physiological
disposition of two kinds of currently incretins-based hypoglycemic
agents GLP-1 agonists and DPP-4 antagonists. As far as our knowledge,
this is the first article that based on incretins-based hypoglycemic
agents’ physiological disposition. There are still some researches need
to be carried out especially on drug interactions, safety use of drugs
on patients with renal impairment and new formulations could improve
pharmacokinetics.