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.