W7 Pharmacokinetics of oral antidiabetics (GP) Flashcards
What do we mean by pharmacokinetics?
Pharmacokinetics is described as what the body does to a drug, refers to the movement of drug into, through, and out of the body (ADME)
Pharmacokinetics of oral drugs
Where does absorption occur?
Metabolism?
Primarily in the intestine
Primarily in the liver
What is an insulin sensitiser?
What is an insulin secretagogue?
- Helps the body respond better to insulin, body becomes sensitive to insulin
- Stimulate the beta cells in the pancreas to secrete insulin
Features of Metformin (for info)
What 2 forms can be prescribed?
- Only biguanide oral antidiabetic agent available
- Used since 1950s
- First-line pharmacologic treatment for T2DM
- Monotherapy or in combination
- Available as tablet or oral liquid
- IR tablets: immediate-release form, which
requires twice-daily dosing (500, 850 and 1,000 mg) - ER tablets: extended-release form, which
requires once-daily dosing (500 and 750 mg)
Absorption of Metformin:
- Absorption – primarily in the small intestine
o 20% of total dose absorbed from the duodenum
o up to 60% from the jejunum and ileum (intestine)
o only very small amounts from the colon - hydrophilic base which exists ay physiological pH as the cationic species
- low intestinal and cell membrane permeability
- organic cation transporters (OCT1)
- plasma membrane monoamine transporter (PMAT)
- oral bioavailability of 40 to 60%
Distribution of Metformin?
Metabolism?
- rapidly distributed
o No binding to plasma proteins
o Liver localisation (concentration 3/4 folds higher than in portal vein)
o primary site of metformin function (inhibition of hepatic glucose output)
o hepatic uptake mediated possibly by organic cation transporters-1 and -3 (OCT1-3) - Metabolism - Metformin is not metabolized
Excretion of Metformin:
- Urine and feces
o Urine (Primarily): renal excretion mediated by specific transporter (Organic Cation Transporter 2 - OCT2)
o Feces: metformin not absorbed in the intestine
Factors effecting high clearance (elimination) of metformin:
o the low molecular weight
o a negligible plasma protein binding
o the presence of transporters in the kidney
o the low lipid solubility which makes negligible the passive reabsorption
12:23
Metformin, clearance
- The high clearance (elimination) of metformin reflects on a half-life of 1.5-4.5 hours
- Remember: half-life is a pharmacokinetic parameter – it’s the time required for a quantity (of substance) to reduce to half of its initial value.
- Drug half-life has important implications for dosing regimen.
- Example: A half-life of 12-48 h is generally ideal for once daily dosing of oral drugs.
- Metformin is taken three times a day, usually with meals.
Drug-Drug interactions of Metformin?
Absorption: Drug transporters (OCT1-3)
* Metformin inhibits histamine and serotonin uptake by OCT1, OCT3 and SERT -> accumulation of serotonin in the gut causing vomiting and diarrhea -> GI side effects seen in metformin-induced GI discomfort (metformin intolerance)
Consider modified-release metformin and slower titration of metformin dose
Thiazolidinediones-Pioglitazone- What are the features?
Absorption?
Distribution?
- Only antihyperglycemic agent of this family
- Improves insulin action mainly by activation of the nuclear peroxisome proliferator-activated receptor-gamma (PPAR-gamma)
- Tablets for oral use (15–30 mg/day), once per day (with or without food)
- Along with metformin/sulfonylurea or insulin therapy.
- Absorption – completely in gastro-intestinal tract
- Distribution – plasma, liver and kidney
- Extensive protein binding (> 97%)
Metabolism of Pioglitazone?
Excretion?
Hepatic cytochrome P450 enzyme system
* CYP2C8 and CYP3A4 (possible drug-drug interactions)
* active metabolites: metabolite II and metabolite IV
(hydroxy derivatives), metabolite III (keto derivative)
- Excretion – in urine (64%) and bile
Sulfonylureas
ADME?
- Stimulate the insulin secretion
- Absorption – well absorbed from the gastrointestinal tract, 2-4hr concentration peak
Food can reduce the absorption of these drugs – so more
effective if given 30 minutes before eating - Distribution – highly bound to plasma proteins (90-99%
binding) - Metabolism – liver
- Excretion – urine
Caution is these drugs are administered to patients with
renal/hepatic insufficiency.
Sulfonylureas
How many generation of sulfonylureas?
Which generation has a longer duration of action?
- Three generations of sulfonylureas related to:
o Half-life (t1/2)
o Duration of action (short, intermediated, long duration)
o Frequency of administration
oSecond generation has longer duration than
first generation
Substitutions on the arylsulfonylurea nucleus
(in red) are large, relatively nonpolar groups (in blue).
Meglitinides (Repaglinide)
- Absorption – well absorbed 56% bioavailability, rapid onset
1 hr concentration peak
-> Drug taken just before each meal (30 min) - Metabolism – liver (via CYP450 2C8 and 3A4, inactive
metabolites) - Excretion – through bile in stool (90%), very small amount
in urine
Dipeptidylpeptidase-4 inhibitors:
What are examples?
- New oral glucose-lowering agents so-called incretin enhancers or gliptins
- Sitagliptin, vildagliptin and saxagliptin then alogliptin and linagliptin
- Long half life -> once-daily administration except for vildagliptin
- Similarly to Saxagliptin (despite short half life), but active metabolite (half DPP-4 inhibition of the parent drug).
- Renal extraction -> dose adjustment in case of renal impairment
- > 80% plasma protein binding (linagliptin)
Gliflozins
Examples?
ADME?
- Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin
- Reversible inhibitors of renal SGLT-2 (Sodium-glucose
cotransporters type 2)
-> reduce glucose reabsorption - Absorption - in the intestine, very high hence excellent oral bioavailability (78%); rapid absorption too (tmax= 1h)
- Dapagliflozin is moderately protein bound (91 %)
- Distribution – kidney primarily
- Metabolism – primary liver, kidney. Inactive 3-O-glucuronide metabolite (60.7%)
- Excretion - 72.0 % in urine and 1.65 % in feces
Acarbose
Drug class?
ADME?
- The only alpha-glucosidase inhibitor available
- Half live of about 2 hours -> taken just before the meals
- Poorly absorbed from the intestine (35%)-> in situ action in the GI tract
-> Reduction of carbohydrates absorption - Metabolism – by intestinal bacteria
-> explaining adverse effects like GI discomforts (bloating
and flatulence) and diarrhea - Excretion – in stool and urine
GLP-1 receptor agonists (GLP-1RA):
MOA?
=Insulin secretagogue
* Incretin hormones are gut peptides that are secreted after nutrient intake and stimulate insulin secretion together with hyperglycemia
* GLP-1 (glucagon-like peptide-1) is one of them
* Incretin analogues or mimetics are used for treatment of T2DM
Peptide drugs
Oral peptide delivery is affected by which factors? (6)
Learn these.
- Ultra-acidic pH in the stomach
- Enzymatic degradation (peptidase) in the GI tract
- Intestinal mucus layer
- Intestinal epithelial cell layer (low permeability)
- GI transit time
- The influence of bile and the microbiome.
Liraglutide
Structure:
- Analogue of glucagon-like peptide 1 (7-37 amino acid)
- Lys34 is replaced by an arginine (R - in purple).
-> resistance to dipeptidyl peptidase–IV (DPP-IV) - C16 acyl chain (palmitoyl lipid moiety - lipidation method) attached to Lys26 via a glutamoyl spacer (E)
-> increase membrane permeability
-> affinity for serum albumin - Peptide–albumin complex is larger than the cut-off for renal ultrafiltration (∼8 nm), hence liraglutide is not readily cleared from circulation until proteolytic cleavage either at the site of lipidation or within the backbone of the peptide occurs
Semaglutide structure:
What is the half life?
What is the frequency of the dose?
- Analogue of glucagon-like peptide 1 (7-37 amino acid)
- amino acids at positions 8 and 34 replaced by α-aminobutyric acid and arginine, respectively (in blue).
-> resistance to dipeptidyl peptidase–IV (DPP-IV) - Lys26 is acylated with stearic diacid.
-> affinity for albumin
-Resistance to DPP-IV
* Half-life (t1/2) of about 1 week
* Once-weekly subcutaneous injection
Oral semiglutide:
What is the frequency of the medication?
- Once-a-day oral tablet version of semaglutide (Rybelsus®) was approved in 2019
- New formulation of Semaglutide (14mg) with an absorption enhancer (SNAC – 300mg)
- SNAC = sodium N-(8-[2-hydroxybenzoyl] amino) caprylate also known as Salcaprozate sodium
- Small-molecule chaperone with excellent safety profile
- 20-year history of achieving better oral bioavailability with products like vitamin B12 and unfractionated heparin
Oral semaglutide
What is the proposed mechanism?
- The pill is taken once awake, in a fast state and with a glass of water
- The tablet arrives in the stomach and dissolves over 60 min
- Pepsin is normally produced from pepsinogen at stomach pH.
- SNAC locally neutralizes the pH, thereby preventing pepsin activation.
- Semaglutide is released from the tablet as
multimers (protected against enzymatic digestion) -
Increase peptide hydrophobicity, possibly as the result of displacement of the water of
hydration or by inducing a more lipophilic conformation
-> which facilitates transcellular absorption across the gastric epithelium - SNAC causes monomers of peptide to be formed.
- SNAC inserts in the plasma membrane of the gastric epithelium and perturbs it via fluidization, but without directly opening tight junctions (TJs).
- Semaglutide fluxes across the epithelium by a transcellular route
Oral peptide development
What are some strategies for improving oral peptide delivery across intestinal epithelia?
- Oral semaglutide (Rybelsus®) is an application of permeation enhancer
- Alternative strategies for improving oral peptide delivery across intestinal epithelia
oPeptide in Nanoparticle
oPeptidase inhibition
oPermeation enhancer (e.g., SNAC)
oBioadhesive Patch
oOther devices
