Pharmacology Update – Canagliflozin


Canagliflozin is a newer anti diabetic drug used in the treatment of Type 2 Diabetes mellitus


Indication Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.Use in type 1 diabetes mellitus patients or in treatment of diabetic ketoacidosis is not recommended.
Mechanism of action Canagliflozin is a Sodium-glucose co-transporter 2 (SGLT2) inhibitor.Sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion.
Pharmacodynamics Canagliflozin binds to SGLT-2 more potently (250-times) than SGLT-1 in vitro. The 50% inhibitory concentrations (IC50) are 2.2-4.4 nmol/L and 684 – 910 nmol/L for SGLT2 and SGLT1 respectively. Dose dependent decreases in renal threshold for glucose and increases in urinary glucose excretion were observed when single and multiple oral doses were administered to type 2 diabetes patients. Decreases in plasma glucose in a dose-dependent fashion were also noted as early as the first day of administration. When given to healthy and type 2 diabetic patients before a meal, a delay in intestinal glucose absorption and a reduction in postprandial glucose was observed. Canagliflozin does not prolong the QTc interval.
Absorption The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. Accumulation in plasma has been observed following multiple doses of 100 – 300 mg. Food does not affect the absorption of canagliflozin. Tmax = 1- 2 hours; Cmax = 1059 – 3148 ng/mL; Time to steady state, once daily dose, 100 – 300 mg = 4-5 days; Absolute oral bioavailability = 65%.
Volume of distribution Steady state, single IV infusion, healthy subject = 119 L. This high value suggests that cangliflozin is extensively distributed to tissue.
Protein binding >99% protein bound, mainly to albumin. It also binds to alpha-acid glycoprotein. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Metabolism Canagliflozin is hepatically metabolized via O-glucuronidation into two inactive O-glucuronide metabolites. The enzymes that facilitate this process are UGT1A9 and UGT2B4. To a lesser extent (7%), canagliflozin also undergoes oxidative metabolism via CYP3A4. Canagliflozin weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes.
Route of elimination Enterohepatic circulation of canagliflozin was negligible. When a single oral dose is administered to a healthy subject, canagliflozin is eliminated via the following: Feces (41.5%, 7.0%, 3.2% as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively). Urine (33%; 30.5% as O-glucuronide metabolite, <1% as unchanged drug).
Half life The apparent terminal half-life (t1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively.
Clearance Mean systemic clearance, healthy subjects, IV administration = 192 mL/min.
Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min.
Toxicity Most common adverse reactions associated with canagliflozin (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination.


Figure describing Mechanism of Action of Canagliflozin

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