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1.
J Pharmacol Exp Ther ; 362(3): 385-394, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28645914

RESUMO

The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Ácidos e Sais Biliares/metabolismo , Cromanos/farmacologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Animais , Bile/metabolismo , Colesterol 7-alfa-Hidroxilase/biossíntese , Colesterol 7-alfa-Hidroxilase/genética , Técnicas de Inativação de Genes , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Troglitazona , Regulação para Cima/efeitos dos fármacos
2.
Biopharm Drug Dispos ; 37(5): 276-86, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27059119

RESUMO

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Bile/metabolismo , Pravastatina/farmacocinética , Ácido Taurocólico/farmacocinética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Anticolesterolemiantes/sangue , Anticolesterolemiantes/farmacocinética , Ácidos e Sais Biliares/metabolismo , Colagogos e Coleréticos/sangue , Colagogos e Coleréticos/farmacocinética , Fígado/metabolismo , Masculino , Pravastatina/sangue , Ratos Sprague-Dawley , Ratos Transgênicos , Ácido Taurocólico/sangue
3.
J Pharmacol Exp Ther ; 357(2): 382-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26907622

RESUMO

Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6- and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7- and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6- to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b(-/-)), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1- to 18.4-fold; P < 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.


Assuntos
Coproporfirinas/sangue , Transportadores de Ânions Orgânicos/genética , Animais , Área Sob a Curva , Ciclosporina/farmacocinética , Células HEK293 , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Macaca fascicularis , Camundongos , Camundongos Knockout , Transportadores de Ânions Orgânicos/administração & dosagem , Transportadores de Ânions Orgânicos/metabolismo , Rifampina/farmacocinética , Rosuvastatina Cálcica/farmacocinética
4.
Bioorg Med Chem Lett ; 25(20): 4412-8, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26386604

RESUMO

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.


Assuntos
Encéfalo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Obesidade/metabolismo , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/química
5.
Bioorg Med Chem Lett ; 25(14): 2793-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26022839

RESUMO

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.


Assuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Meia-Vida , Humanos , Obesidade/tratamento farmacológico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Perda de Peso/efeitos dos fármacos
6.
J Med Chem ; 57(18): 7509-22, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25165888

RESUMO

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).


Assuntos
Fármacos Antiobesidade/farmacologia , Descoberta de Drogas , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Masculino , Ratos
7.
Xenobiotica ; 44(12): 1108-16, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24947446

RESUMO

1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats.


Assuntos
Envelhecimento/fisiologia , Fígado/irrigação sanguínea , Fígado/metabolismo , Obesidade/metabolismo , Animais , Células Cultivadas , Gorduras na Dieta/efeitos adversos , Meia-Vida , Hepatócitos/metabolismo , Obesidade/etiologia , Ratos , Ratos Sprague-Dawley
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