Pharmacokinetics of oral anti diabetics (emerging oral peptides)

Oral anti diabetic drugs

• insulin sensitisers

• insulin secretagogues

• miscellaneous

insulin sensitisers

• Biguanides

• thiazolidinediones

Insulin secretagogues

• sulfonylureas

• meglitindes

• incretin analogues

• glisten

miscellaneous

• gliflozin

• acarbose

metformin

• only biguanide oral anti diabetic agent available

• used since 1950s

• first line pharmacological treatment for T2DM

• monotherapy or in combination

• available as tablet or oral liquid

metformin absorption

• primarily in the small intestine

• 20% of total dose absorbed from the duodenum

• up to 60% from the jejunum and ileum

• only very small amount from the colon

metformin distribution

• rapidly distributed

• no binding to plasma proteins

• liver localisation

• primary site of metformin function (inhibition of glucose output)

• primary site of metformin function (inhibition of glucose output)

• hepatic uptake mediated possibly by organic cat transporters -1 and -3

metformin metabolism

• metform is not metabolism

metformin exertion

• urine and feces

• urine- renal excretion mediated by specific transporter

• feces- metformin not absorbed in the intestine factors effecting high cleanse

• low molecular weight

• a negligible plasma protein binding

• the presence of transporter in the kidney

metformin

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. This is supported

by the high clearance and therefore short half-life.

drug drug interactions

• absorption: Drug transporters

• metformin inhibits histamine and serotonin uptake → accumulation of serotonin in the gut causing vomiting and diarrhoea→ GI side effects seen in metformin induced GI discomfort

• consider modified release metformin and slower titrametformin dose

pioglitazone

• only antihyperglycemic agent of this family

• improves insulin action mainly by activation of the nuclear peroxisome proliferator activated receptor gamma

• tablet for oral use, once per day

• along with metformin/ sulfonylurea or insulin therapy

Pioglitazone absorption

• completely in gastro intestinal tract

Pioglitazone distribuiton

• plasma, liver and kidney

  • extensive protein binding

Pioglitazone metabolism

• hepatic cytochrome P450 enzyme system

• CYP2C8 and CYP3A4

• active metabolites

Pioglitazone excretion

• in urine and bile

sulfonylureas

• stimulate the insulin secretion

• these drugs are administered to patients with renal/ hepatic insufficiency

• Three generations of sulfonylureas related to:

  o Half-life (t1/2)

  o Duration of action (short, intermediated,

  long duration)

  o Frequency of administration will depend on

  the duration of action of each drug

Sulfonylureas absorption

• well absorbed from the gastrointestinal tract, 2-4 hr concentration peak food can reduce the absorption of these drugs- so more effective if given 30 minutes before eating

Sulfonylureas distribution

• highly bound to plasma proteins

Sulfonylureas metabolism

liver

Sulfonylureas excretion

• urine

meglitinides absorption

• well absorbed 56% bioavailability, rapid onset 1hr conc peak

  • drug taken just before each meal

Meglitinides metabolsim

• liver

Meglitinides excretion

• through bile in stool, very small amount in urine

Dipeptidylpeptidase-4 inhibitors

• new oral glucose- lowering agents so called incretin enhancer or glistens

• 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% plasm protein

  binding (linagliptin)

Glifozins

Canagliflozin, Dapagliflozin, Empagliflozin, Ertugliflozin

• Reversible inhibitors of renal SGLT-2 (Sodium-glucose

cotransporters type 2)

-> reduce glucose reabsorption

Glifozins absorption

• in the intestine, very high hence excellent oral bioavailability

• dapagliflozin is moderately protein bound

glifozins distribution

• kidney primarily

Glifozins metabolism

• primarily liver, kidney, inactive 3-0 glucuronide

Glifozins exceretion

• 72% in urine and 1.65% in feces

acarbose

The only alpha-glucosidase inhibitor available

• Half live of about 2 hours -> taken just before the meals

• Poorly absorbed from the intestine (35%)

acarbose absorption

• from the intestine in situ action in GI tract

acarbose metabolism

• intestinal bacteria

  • explaining adverse effects like GI discomfort and diarrhoea

acarbose excretion

• in stool and urine

GLP-1 receptor agonists

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 durgs

Oral peptide delivery is affected by:

• 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

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

semaglutide

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 semaglutide

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

proposed mechanism

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

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

oral insulin

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

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

advantages of oral insulin

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