W7 Pharmacokinetics of oral antidiabetics (GP) Flashcards

1
Q

What do we mean by pharmacokinetics?

A

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)

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2
Q

Pharmacokinetics of oral drugs
Where does absorption occur?
Metabolism?

A

Primarily in the intestine
Primarily in the liver

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3
Q

What is an insulin sensitiser?
What is an insulin secretagogue?

A
  • Helps the body respond better to insulin, body becomes sensitive to insulin
  • Stimulate the beta cells in the pancreas to secrete insulin
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4
Q

Features of Metformin (for info)
What 2 forms can be prescribed?

A
  • 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)
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5
Q

Absorption of Metformin:

A
  • 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%
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6
Q

Distribution of Metformin?
Metabolism?

A
  • 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
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7
Q

Excretion of Metformin:

A
  • 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

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8
Q

Metformin, clearance

A
  • 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.
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9
Q

Drug-Drug interactions

A

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

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10
Q

Thiazolidinediones-Pioglitazone- What are the features?
Absorption?
Distribution?

A
  • 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%)
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11
Q

Metabolism of Pioglitazone?
Excretion?

A

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
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12
Q

Sulfonylureas
ADME?

A
  • 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.
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13
Q

Sulfonylureas
How many generation of sulfonylureas?
Which generation has a longer duration of action?

A
  • 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).

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14
Q

Meglitinides (Repaglinide)

A
  • 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
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15
Q

Dipeptidylpeptidase-4 inhibitors:
What are examples?

A
  • 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)
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16
Q

Gliflozins
Examples?
ADME?

A
  • 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
17
Q

Acarbose
Drug class?
ADME?

A
  • 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
18
Q

GLP-1 receptor agonists (GLP-1RA):
MOA?

A

=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

19
Q

Peptide drugs
Oral peptide delivery is affected by which factors? (6)
Learn these.

A
  • 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.
20
Q

Liraglutide
Structure:

A
  • 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
21
Q

Semaglutide structure:
What is the half life?
What is the frequency of the dose?

A
  • 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

22
Q

Oral semiglutide:
What is the frequency of the medication?

A
  • 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
23
Q

Oral semaglutide
What is the proposed mechanism?

A
  • 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
24
Q

Oral peptide development
What are some strategies for improving oral peptide delivery across intestinal epithelia?

A
  • 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
25
Q

Oral insulin (for info)
no need to memorise it was skipped

A
  • Permeation enhancers and peptidase inhibition have been used to prepare oral formulations of insulin
  • ORMD-0801 = enteric-coated formulation of insulin designated as the
    Protein Oral Delivery (POD ) technology
  • Main components are:
    o Ethylenediaminetetraacetate sodium (EDTA) - (goal: calcium-chelating, TJ
    opening and membrane perturbation)
    o Bile salts and omega-3 fatty acids (goal: mild detergent surfactant actions)
    o Peptidase inhibitors (goal: stop peptide enzymatic digestion)
  • This product is under development (under phase II clinical trial)
26
Q

Oral insulin ll (for info)
no need to memorise it was skipped

A
  • Another oral insulin analogue developed using the hybrid PEGalkylation strategy
  • Functionalisation of the lysine (B-chain) with amphiphilic oligomer (<500
    Da). Hydrolysis of the oligomer release the native structure
  • Containing both a water-soluble polyethylene glycol (PEG) moiety and lipid-
    soluble alkyl chain
  • Advantages of this technology:
  • Resist enzyme digestion -> Enhance stability in vivo
  • Easy translocation over the gastric mucosa into the bloodstream -> increase membrane permeation
  • Currently under study (Phase IV)
27
Q

All the aspects listed below can affect the delivery of oral peptides EXCEPT ONE. Please identify the outlier:
* Intestinal mucus layer
* Ultra-acid pH in the stomach
* Enzymatic degradation in the GI tract
* Kidney dysfunction
* Influence of bile and the microbiome

A

= Kidney dysfunction

28
Q
A