Mechanism of Action

●    Luseogliflozin is an inhibitor of SGLT2, which is the major transporter involved in the reabsorption of glucose in kidneys.

●    Luseogliflozin selectively inhibited hSGLT2 (K_i = 1.10 nM, IC₅₀ = 2.26 nM, selectivity >1200 fold for hSGLT1 ), resulting in decrease of renal glucose re-absorption, and thereby increasing urinary glucose excretion (UGE) and lowering plasma glucose (PG) in patients with type 2 diabetes.

●    The metabolites had a pharmacological profile similar to luseogliflozin on inhibiting SGLT2 with less potent (M2, IC₅₀ = 4.01 nM; M17, IC₅₀ =201 nM).

●    Luseogliflozin showed very faint ligand binding inhibition activity in a panel of 3 types of transporter, 5 types of ion channel and 6 types of receptor up to 100 µM, except Na⁺ channel site 2 (66.96% inhibition at 100 µM) and Neurokinin 1 (58.75% inhibition at 100 µM).

In Vivo Efficacy

●    Increased urinary glucose excretion (UGE):

v    db/db mosue: MED = 1 mg/kg.

v    ZDF diabetic rats: MED = 0.3 mg/kg.

v    DIO rats: MED = 3 mg/kg.

v    Beagle dogs: MED = 150 µg/kg/h for infusion, and 0.03 mg/kg after OGTT.

●    Decreased blood glucose concentration and blood glucose AUC:

v    db/db mice: Significantly reduced AUC_0-8h at ≥0.3 mg/kg (single dose) and blood glucose levels at ≥3 mg/kg (QD × 4 weeks).

v    ZDF rats: Significantly decreased blood glucose concentration and AUC_0-2h at ≥3 mg/kg in OGTT.

v    STZ SD rats:

Ø    Significantly reduced plasma glucose levels and AUC_0-8h at ≥0.3 mg/kg (single dose).

Ø    Significantly reduced plasma glucose levels at ≥0.001% mixed in diet for 4 weeks.

v    Non-diabetic SD rats: Significantly reduced plasma glucose levels at 1 mg/kg (no-fasted) and 3 mg/kg (fasted).

●    Improved Pancreatic β cell protection and insulin secretion:

v    STZ diabetic SD rats: MED = 0.01%.

●    Decreased GHb level:

v    db/db mice: Significant at 3mg/kg.

v    GK Non-fatty diabetic rats: Significant at 0.002%.

v    STZ diabetic SD rats: Significant at 0.001%.

Absorption of Luseogliflozin

●    Had a moderate oral bioavailability in male rats (30.3%-37.8%), but high in dogs (92.7%-101.6%) and female rats (58.2%).

●    Was absorbed rapidly (T_max = 0.5-1.33 h) in rats and dogs, but rapidly to moderately in humans.

●    Showed a half-life of 9.23-13.8 h in humans, much longer than those in rats (2.52-4.51 h) and dogs (3.84-4.25 h), after oral administration.

●    Had a moderate clearance in rats (1.61-2.18 L/h/kg), but low dogs (0.19 L/h/kg), compared to the liver blood flow, after intravenous administration.

●    Exhibited an extensive tissue distribution in rats, but moderate in dogs, with apparent volumes of distribution at 2.63-2.88 and 0.8 L/kg, respectively, after intravenous administration.

●    Showed a high permeability, with a Papp_(A→B) of 14 × 10^-6 cm/s at 10 μM in Caco-2 cell monolayer model.

Distribution of Luseogliflozin

●    Exhibited high plasma protein bindings (96.0%-96.3%) in humans and all nonclinical species.

●    Had a blood cell association of 4.8%-6.9% in humans, suggesting little penetration into red blood cells.

●    Rats after oral administration:

v    The drug was rapidly and well distributed into most tissues except for the central nervous system (CNS), with little or no radioactivity in brain.

v    Relatively higher concentration levels were observed in small intestine, stomach, kidneys, lungs and liver, compared to other organs.

v    Radioactivity concentrations decreased below the lower limit of quantification in all tissues at 168 h post-dose.

v    The distribution of luseogliflozin in male rats was similar to female rats.

Metabolism of Luseogliflozin

●    Could be largely metabolized in rat and monkey hepatocytes, but little in monkey and human hepatocytes.

●    CYP3A4 was the major metabolizing enzymes, with 4A11, ADL and ALDH involved in the metabolism of luseogliflozin.

●    Overall, the parent drug represented the most abundant component, with M2 as the major metabolite in human plasma.

Excretion of Luseogliflozin

●    Was predominantly eliminated in feces in humans.

●    Was predominantly eliminated in feces in rats and dogs, but urine in monkeys.

●    About 75.8%-76.6% of luseogliflozin was recovered via biliary excretion in bile duct-cannulated (BDC) rats.

Drug-Drug Interaction

●    Luseogliflozin weakly inhibited CYP2C19, but did not inhibit other human CYP450 enzymes.

●    Luseogliflozin was not an inducer of CYP3A4, CYP1A2 or CYP2B6.

●    Luseogliflozin was a substrate of P-gp, but not of OATP1B1, OATP1B3, OAT1, OAT3 or OCT2.

●    Luseogliflozin did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3 or OCT2.

Single-Dose Toxicity

●    Luseogliflozin exhibited low acute toxicity by the oral route both in rodent and non-rodent species:

v    Rat ALD: >2000 mg/kg.

v    Dog ALD: >1500 mg/kg.

Repeated Dose Toxicity

●    Sub- and chronic toxicological risk in rats (up to 26 weeks), dogs (up to 52 weeks) and monkeys (up to 13 weeks).

v    Pronounced side reactions were noted at non-lethal dose levels in all tested species，including erosion of glandular stomach/duodenum (rat), lower body weight (rat, dog), and loose stools/diarrhea (dog).

v    Based on the longest studies employed, safety margin in rodents was much closer to even below 1.0, while in non-rodents was far beyond, i.e., 4.5- to 5.5 fold for dogs, 20.7- to 25.5 fold for monkeys.

Safety Pharmacology

●    Not much of special concern on CNS, cardiovascular, respiratory and gastrointestinal tract functions.

Genotoxicity

●    Luseogliflozin, M2 and M17 get least potential for mutagenicity, clastogencity or direct DNA damage, based on the standard battery of genotoxicity studies plus unscheduled DNA synthesis assay.

Reproductive and Developmental Toxicity

●    Rat fertility and early embryonic development: NOAEL = 300 mg/kg (male) and 100 mg/kg (female).

●    Embryo-fetal development: Rat NOAEL = 50 mg/kg, while rabbit NOAEL = 1000 mg/kg.

●    Pre- and postnatal development: NOAEL was determined as 50 mg/kg.

●    Luseogliflozin distributed to placenta and fetus in pregnant rats, migrated radioactivity was less than 0.1%.

●    Milk excretion of luseogliflozin was also found in lactating rats, milk/plasma ratio at 1-24 h postdose ranged from 0.27 to 1.54.

Carcinogenicity

●    Luseogliflozin was of no potential for carcinogenicity.