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1.
Drug Res (Stuttg) ; 69(6): 314-322, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30103216

RESUMO

PURPOSE: Tofogliflozin is an orally available selective inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus (T2DM). Two studies were conducted to evaluate the effect of renal impairment on pharmacokinetics and pharmacodynamics of tofogliflozin. METHODS: The studies were: 1) single dose study in T2DM patients with normal renal function and mild, moderate and severe renal impairment, and 2) multiple dose study for 24 weeks in T2DM patients with normal renal function and moderate renal impairment. RESULTS: Renal function did not have a clinically relevant effect on the PK of tofogliflozin. Urinary glucose excretion up to 24 h after administration of tofogliflozin (UGE24h) decreased with decreasing glomerular filtration rate. Lowering UGE24h resulted in waning glycemic control but not body weight reduction. CONCLUSIONS: Single and multiple administrations of tofogliflozin were generally well tolerated in T2DM patients with various renal functions. As far as investigated here, these studies indicate no dose adjustment is required for patients with renal impairment.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Glucosídeos/farmacologia , Insuficiência Renal Crônica/fisiopatologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Adulto , Idoso , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/urina , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular , Glucosídeos/uso terapêutico , Glucosídeos/urina , Humanos , Masculino , Pessoa de Meia-Idade , Eliminação Renal/fisiologia , Insuficiência Renal Crônica/etiologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/urina
2.
Drug Res (Stuttg) ; 67(6): 349-357, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28427104

RESUMO

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t1/2 of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased Cmax by approximately 30% but did not change AUC0-inf. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE0-24h), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (Cavg) and UGE0-24h fitted Emax model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL Cavg corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.


Assuntos
Compostos Benzidrílicos/administração & dosagem , Glucose/metabolismo , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Área Sob a Curva , Povo Asiático , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/farmacologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Japão , Masculino , Transportador 2 de Glucose-Sódio , População Branca , Adulto Jovem
3.
Endocrinology ; 157(3): 1029-42, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26713783

RESUMO

Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic ß-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to ß-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Resistência à Insulina , Lipólise/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/sangue , Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Técnica Clamp de Glucose , Corpos Cetônicos/sangue , Lipase/efeitos dos fármacos , Lipase/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Esterol Esterase/efeitos dos fármacos , Esterol Esterase/metabolismo , Aumento de Peso/efeitos dos fármacos
4.
Xenobiotica ; 45(3): 230-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25350082

RESUMO

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.


Assuntos
Compostos Benzidrílicos/metabolismo , Glucosídeos/metabolismo , Hepatócitos/metabolismo , Metabolômica/métodos , Microssomos Hepáticos/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/química , Radioisótopos de Carbono , Coenzimas/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Interações Medicamentosas , Indução Enzimática/efeitos dos fármacos , Glucosídeos/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Humanos , Concentração Inibidora 50 , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Ligação Proteica/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Fatores de Tempo
5.
J Pharmacol Exp Ther ; 345(1): 52-61, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23386251

RESUMO

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 (Ki) 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 = 0.985; P < 0.05), with in vivo Ki 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.


Assuntos
Hipoglicemiantes , Modelos Biológicos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Transporte Biológico , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Glucose/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Masculino , Estrutura Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transportador 2 de Glucose-Sódio , Espectrometria de Massas em Tandem
6.
Am J Physiol Endocrinol Metab ; 304(4): E414-23, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23249697

RESUMO

To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20-50% with phlorizin and by 1-5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg⁻¹·min⁻¹ and increased EGP by 1-2 mg·kg⁻¹·min⁻¹, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg⁻¹·min⁻¹ and increased EGP by about 4 mg·kg⁻¹·min⁻¹; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Glucosídeos/efeitos adversos , Glicosúria/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Rim/efeitos dos fármacos , Bloqueadores dos Canais de Sódio/efeitos adversos , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Absorção/efeitos dos fármacos , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacocinética , Compostos Benzidrílicos/uso terapêutico , Glicemia/análise , Creatinina/metabolismo , Creatinina/urina , Relação Dose-Resposta a Droga , Gluconeogênese/efeitos dos fármacos , Glucosídeos/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/uso terapêutico , Glicosúria/etiologia , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/urina , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemia/metabolismo , Hipoglicemia/urina , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Rim/metabolismo , Masculino , Florizina/administração & dosagem , Florizina/efeitos adversos , Florizina/farmacocinética , Florizina/uso terapêutico , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/uso terapêutico , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
7.
J Pharm Sci ; 101(11): 4347-56, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22927193

RESUMO

The purpose of this study is to characterize the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) of sodium-glucose cotransporter (SGLT) inhibitors. PK-PD studies of SGLT inhibitors (CH4941527 and T-1095), which have different half-life and selectivity to SGLT2, were performed using db/db mice. The time courses of compound concentration in plasma, blood glucose (BG), and renal glucose excretion were measured after a single oral administration of each SGLT inhibitor. An indirect-response PK-PD model was developed, in which it was assumed that an SGLT inhibitor enhances renal glucose excretion and the enhanced glucose excretion reduces BG. In the PK-PD study, both SGLT inhibitors increased renal glucose excretion and reduced BG in a dose-dependent manner. The present PK-PD model could suitably capture the effect of SGLT inhibitors and the effect shown suggested that the BG reduction could be explained by the enhanced renal glucose excretion. There were no great differences in the estimated PD parameters between the two inhibitors and they were comparable to the data from previously reported pharmacological studies. The present PK-PD model is helpful for understanding the plasma concentration-dependent effect of SGLT inhibitors on renal glucose excretion and BG.


Assuntos
Glicemia/análise , Rim/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Animais , Camundongos , Modelos Teóricos
8.
J Med Chem ; 55(17): 7828-40, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22889351

RESUMO

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Compostos Benzidrílicos/química , Compostos Benzidrílicos/farmacocinética , Glucosídeos/química , Glucosídeos/farmacocinética , Humanos , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Transportador 2 de Glucose-Sódio , Espectrometria de Massas por Ionização por Electrospray
9.
Bioorg Med Chem ; 20(13): 4117-27, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22652255

RESUMO

C-Aryl 5a-carba-ß-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.


Assuntos
Cicloexanóis/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/análogos & derivados , Hipoglicemiantes/química , Inibidores do Transportador 2 de Sódio-Glicose , Administração Oral , Animais , Área Sob a Curva , Glicemia/análise , Cicloexanóis/farmacocinética , Cicloexanóis/uso terapêutico , Glucose/farmacocinética , Glucose/uso terapêutico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Obesos , Transportador 2 de Glucose-Sódio/metabolismo , Relação Estrutura-Atividade
10.
J Pharmacol Exp Ther ; 341(3): 692-701, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22410641

RESUMO

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.


Assuntos
Compostos Benzidrílicos/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Hemoglobinas Glicadas/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Intolerância à Glucose/tratamento farmacológico , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/sangue , Hiperglicemia/tratamento farmacológico , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-Dawley , Ratos Zucker
11.
Bioorg Med Chem ; 19(18): 5334-41, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21873071

RESUMO

5a-Carba-ß-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/análogos & derivados , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Glucose/síntese química , Glucose/química , Glucose/farmacologia , Masculino , Camundongos , Camundongos Obesos , Conformação Molecular , Dados de Sequência Molecular , Transportador 2 de Glucose-Sódio/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
12.
Drug Metab Dispos ; 39(10): 1801-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21712434

RESUMO

A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor.


Assuntos
Glucose/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Florizina/farmacologia , Florizina/farmacocinética , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Transporte Biológico/efeitos dos fármacos , Glicemia/metabolismo , Masculino , Modelos Biológicos , Dinâmica não Linear , Ratos , Ratos Sprague-Dawley , Sódio/metabolismo , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Vesículas Transportadoras/efeitos dos fármacos , Vesículas Transportadoras/metabolismo
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