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1.
Pharm Res ; 38(5): 901-914, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33880721

RESUMO

PURPOSE: The use of two solvent-casted film methods to select optimal polymer compositions for amorphous solid dispersions prepared to support preclinical pharmacokinetic and toxicology studies is described. METHODS: Evaporation of solvent from cover slips by using nitrogen flow, and solvent removal from vials by using rotary evaporation were employed. The films prepared on cover slips were evaluated under the microscope to determine crystallinity. The methods were validated by scaling up corresponding SDDs, evaluating SDD's dissolution, and comparing those results to the dissolution of drug-polymer films. Subsequently, SDD suspensions were prepared and dosed orally to rats to determine pharmacokinetic parameters. This was done by using three compounds from our pipeline and evaluating multiple polymers. RESULTS: The dissolution of generated films showed good agreement with the dissolution of spray dried dispersions when the films were fully amorphous (Compound A and B). In contrast, there was disagreement between film and SDD dissolution when the films had crystallized (Compound C). The in vivo exposure results indicated that the polymer choice based on the film screening methods would have been accurate for drug-polymer films that were amorphous (Compound A and B). Two additional case studies (Compound D and E) are presented, showing good agreement between in vivo and in vitro results. CONCLUSION: This study established the ability of two film casting screening methods to predict the in vitro and in vivo performance of corresponding SDDs, provided that the films are fully amorphous.


Assuntos
Composição de Medicamentos/métodos , Polímeros/química , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Ratos , Solubilidade , Solventes/química , Testes de Toxicidade/métodos , Difração de Raios X
2.
J Pharmacol Exp Ther ; 362(3): 385-394, 2017 09.
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
3.
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
4.
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
6.
Bull Menninger Clin ; 73(3): 188-202, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19807223

RESUMO

Psychological assessment supervision requires the application of technical, conceptual, and interpersonal interventions that address the supervisee's skills, knowledge, and ethical competencies. This article discusses assessment domains that are fundamental to helping trainees refine technical and reasoning skills, and utilizes Jacob, David, and Meyer's (1995) application of Johnson-Laird's (1988) typology of thought as a supervisory technique that encourages the supervisee's inductive, associative, creative, and self-reflective thinking in response to clinical situations. A clinical illustration is presented.


Assuntos
Competência Clínica , Relações Interprofissionais , Liderança , Psicoterapia/educação , Humanos , Transtornos Mentais/terapia , Gestão de Recursos Humanos , Preceptoria , Papel Profissional , Relações Profissional-Paciente
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