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

Yamaguchi, Koji; Kato, Motohiro; Suzuki, Masayuki; Hagita, Hitoshi; Takada, Maiko; Ayabe, Miho; Aso, Yoshinori; Ishigai, Masaki; Ikeda, Sachiya

doi:10.1124/jpet.113.203125

Cited by 17 publications

(6 citation statements)

References 35 publications

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“…Several mathematical models describing SGLT2 inhibitors are also presented. For example, three models describe the pharmacokinetics (PK) and pharmacodynamics (PD) of SGLT2 inhibitors in animals (Yamaguchi et al, 2011 , 2012 , 2013 ), two population PK models exist for empagliflozin (Riggs et al, 2013 ) and dapagliflozin (van der Walt et al, 2013 ), and Maurer et al ( 2011 ) describes a PK/PD model for dapagliflozin in rats and humans. However, a model that describes the concentration of SGLT2 inhibitors at the potential site of action (i.e., the lumen of proximal tubule in the kidneys) is yet to be published.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

2014

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The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family).

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Section: Introductionmentioning

confidence: 99%

Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

2014

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“…Although previous studies have reported particular PK-PD models to evaluate the UGE of SGLT2 inhibitors, [13][14][15][16][17][18][19] only four have adopted the mechanism-based PK-PD models: the PK-PD model for tofogliflozin in rats 16,17) and the PK-PD model of dapagliflozin and canagliflozin in humans. 18,19) In these studies, the investigators adopted the physiological construction of the proximal tubule in the kidney and the kinetics of competitive SGLT1/2 inhibition in their PK-PD model and successfully described the time course of UGE.…”

Section: )mentioning

confidence: 99%

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

Samukawa

Mutoh

Chen

et al. 2017

Biological & Pharmaceutical Bulletin

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Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, K on and K off , and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (K i2 ) and inhibition-rate constants for SGLT2 (K on and K off ) were 0.31-and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from K off , 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.Key words luseogliflozin; urinary glucose excretion; pharmacokinetic-pharmacodynamic model; sodium glucose co-transporter 2; type 2 diabetes mellitus In the human kidney, plasma glucose entering the glomeruli is filtered into the nephron fluid, and the filtered glucose is reabsorbed almost completely by two isoforms of sodium glucose co-transporter (SGLT), SGLT2 and SGLT1. SGLT2 is a high-capacity, low-affinity glucose transporter located in the early convoluted segment (S1 segment) of the proximal tubule that mediates 90% of renal glucose reabsorption. SGLT1 is a high-affinity, low-capacity glucose transporter located in the straight section of the proximal tubule (S3 segment) that is responsible for 10% of renal glucose reabsorption. 1) Inhibition of SGLT2 causes glucose excretion in urine and a reduction in plasma glucose. Several SGLT2 inhibitors have been developed for treatment of type 2 diabetes mellitus (T2DM). 2-4)Luseogliflozin is a novel selective SGLT2 inhibitor 5,6) currently marketed for the treatment of T2DM. The recommended dose is 2.5 mg (or 5 mg depending on the symptoms) once daily before or after breakfast. Studies in Japanese patients with T2DM have confirmed that treatment with luseogliflozin increases urinary glucose excretion (UGE) and reduces plasma glucose levels. [7][8][9][10][11][12] In a clinical pharmacology study conducted in Japanese patients with T2DM, reported by Sasaki et al., intensive sampling of UGE (nine sampling intervals a day) was performed and UGE ...

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“…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). Additionally, long-term use of tofogliflozin in T2DM patients possibly prevents the progression of diabetic nephropathy (Nagata et al, 2013b).…”

Section: Introductionmentioning

confidence: 99%

“…Considering these risks, it is essential for new anti-diabetics to have no potential of DDI. Yamaguchi et al (2013) reported that renal glucose reabsorption correlates with the plasma concentration of an SGLT inhibitor. This suggests that any factors that alter the pharmacokinetics of an SGLT inhibitor would possibly affect its therapeutic efficacy.…”

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

Cited by 17 publications

References 35 publications

Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

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

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