Tofogliflozin, a Potent and Highly Specific Sodium/Glucose Cotransporter 2 Inhibitor, Improves Glycemic Control in Diabetic Rats and Mice

Suzuki, Masayuki; Honda, Kazuo; Fukazawa, Motoharu; Ozawa, Kazuharu; Hagita, Hitoshi; Kawai, Takahiro; Takeda, Minako; Yata, Tatsuo; Kawai, Mio; Fukuzawa, Taku; Kobayashi, Takamitsu; Sato, Tsutomu; Kawabe, Yojiro; Ikeda, Sachiya

doi:10.1124/jpet.112.191593

Cited by 138 publications

(122 citation statements)

References 35 publications

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“…These compounds also have the potential to inhibit SGLT1 slightly. Although luseogliflozin has a relatively high selectivity for SGLT2 compared with similar kinds of drugs (Suzuki et al, 2012), the value of [I 2 ], which represents the concentration of inhibitor in the gastrointestinal tract arising from the highest approved clinical dose (5 mg) dissolved in 250 ml of water, was much higher than the 50% inhibitory concentration (IC 50 ) value for SGLT1 (SGLT IC 50 ). The value of [I 2 ]/SGLT1 IC 50 was higher than 10, which is the value used as a decision criterion for performing a clinical DDI study as mentioned in the current FDA DDI draft guidance.…”

Section: Introductionmentioning

confidence: 96%

“…Miglitol, an a-glucosidase inhibitor, is absorbed via SGLT1 and is a widely prescribed drug for the treatment of type 2 diabetes mellitus; miglitol acts by influencing carbohydrate digestion to blunt the postprandial blood glucose increase (Sels et al, 1999). Luseogliflozin is a novel and potent selective SGLT2 inhibitor (Kakinuma et al, 2010;Suzuki et al, 2012;Washburn and Poucher, 2013) that is used orally for the treatment of type 2 diabetes. Selective SGLT2 inhibitors for type 2 diabetes are now receiving special attention because of their novel and safe mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

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A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

et al. 2014

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A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC 50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol T max (time for C max ) value (TAIC/T max ). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/T max in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/T max in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

et al. 2014

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“…An in vitro SGLT2 inhibition experiment was conducted as described in the literature (Suzuki et al, 2012). In brief, human SGLT2 (hSGLT2) cDNA was cloned into pcDNA3.1, and the constructed expression vector was introduced into CHO-K1 cells to establish a cell line expressing hSGLT2.…”

Section: Sglt Inhibition Studiesmentioning

confidence: 99%

“…These reports indicate that SGLT2 plays an important role in renal glucose reabsorption and is a promising novel target for diabetes mellitus therapy. Suzuki et al (2012) reported that tofogliflozin lowered blood glucose levels by potently inhibiting renal SGLT2 in diabetic rats and mice and improved their pathological conditions of T2DM. In contrast, tofogliflozin showed no glucose-lowering effect in hypo/euglycemic conditions because its inhibition of SGLT2 is highly specific (Nagata et al, 2013a;Yamaguchi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

In vitroprofiling of the metabolism and drug–drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP

Yamane¹,

Kawashima²,

Yamaguchi³

et al. 2014

Xenobiotica

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Ishigai (2015) In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP, Xenobiotica, 45:3, 230-238, DOI: 10.3109/00498254.2014 RESEARCH ARTICLEIn vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP Project & Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan Abstract 1. The metabolism and drug-drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs. 2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1. 3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency.

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“…Tofogliflozin is a highly potent and selective SGLT2 inhibitor (Ohtake et al, 2012;Suzuki et al, 2012) and is currently in a phase III trial for type II diabetes mellitus treatment. We used tofogliflozin and other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2 as the test compounds and performed pharmacokinetic and pharmacodynamic (PK-PD) studies of them with use of normal rats.…”

Section: Introductionmentioning

confidence: 99%

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Yamaguchi

Kato

Suzuki

et al. 2013

J Pharmacol Exp Ther

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To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (K i ) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r 5 0.985; P , 0.05), with in vivo K i values for SGLT2 in the range of 0.3-3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.

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Tofogliflozin, a Potent and Highly Specific Sodium/Glucose Cotransporter 2 Inhibitor, Improves Glycemic Control in Diabetic Rats and Mice

Cited by 138 publications

References 35 publications

A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

In vitroprofiling of the metabolism and drug–drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

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