Dapagliflozin

Category/Class :  Sodium Glucose Co-transporter 2 (SGLT2) Inhibitors 

Mechanism of Action :  Ninety percent of the glucose re-absorption occurs through SGLT2 in the proximal convoluted tubule 

Inhibition of SGLT2: result in glucose excretion of only 30–50% of the amount filtered 

Drugs: dapagliflozin, canagliflozin, empagliflozin 

Pharmacokinetics : 

• A: rapidly absorbed by the GI tract.

• elimination half-life of dapagliflozin is 10–12 hours

• E: 70% of the given dose is excreted in the urine in the form of 3-O-glucuronide 

 

Contraindications : not recommended in patients with more severe renal failure or advanced liver disease  

Drug interaction : 

• Angiotensin II has been shown to induce SGLT2 production via the AT1 receptor. Thus, blockade of the renin-angiotensin- aldosterone axis may result in lower SGLT2 availability.

• Concomitant rifampin administration reduces the total exposure to dapagliflozin by 22%

 

Primary and Secondary Pharmacology

In drug discovery research, the objectives of pharmacologystudies are to demonstrate the biologic activity (efficacy and selectivity) ofa new molecule entity (NME) against the targeted disease, and to provide data for safety evaluation. Thus, pharmacology studies can be divided into three categories: Primary pharmacodynamic (or primary pharmacology), Secondary pharmacology and Safety pharmacology studies.
Studies on the mode of action and/or effects of a test substance in relation to its desired therapeutic target are Primary Pharmacodynamics. Assessments of new drugs for pharmacological activities other than the desired therapeutic target are called Secondary Pharmacology. The third category, Safety Pharmacology studies investigate the potential undesirable pharmacodynamic effects of a test substance on physiological function of one ormore organ systems in relation to exposure in the therapeutic range and above.Thus, safety pharmacology studies contribute to risk assessment and patient management. For those who are interested in knowing more on Safety pharmacology studies may consult ICH guidance S7A (CNS, respiratory and CVS) and S7B (proarrhythmic risk)
(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm).
Sufficient information is not readily available on secondary pharmacology target (or off-target activity) of NME. E.g., agonist activity ofa NME to 5-HT2B receptors on heart valve leaflets is known to cause fibrotic cardiac valvulopathy. Ergot alkaloid (ergotamine), MDMA (ecstasy) has partial agonist activity toward this receptor. For more information, readers may read this review article, an excellent source of information on secondary pharmacology targets screening for a NME:
Bowes, J. et al. Reducing safety-related drug attrition: theuse of in vitro pharmacological profiling. Nature Rev. Drug Discov. 11, 909–922(2012).
In the recent issue of NatureDrug Discovery, we have discussed the usefulness of potential off-targetactivity of NMEs. These data may be made available along with primarypharmacology data to support first in human clinical trials.http://www.nature.com/nrd/journal/v14/n4/full/nrd3845-c1.html?WT.ec_id=NRD-201504