Influência da exposição ao tolueno por inalação na atividade In Vivo dos transportadores da família Oatp em ratos
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Data
2016-07-20
Autores
Mauro, Mariana [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
A exposição ocupacional a agentes químicos é potencialmente capaz de modificar a disposição cinética ou o metabolismo de fármacos, principalmente em função da indução ou inibição de enzimas do sistema citocromo P450. Entretanto, estudos que mostram o efeito da exposição ocupacional a agentes químicos na atividade de transportadores de fármacos são escassos. O tolueno está presente no ambiente de trabalho principalmente na forma de vapor. Neste ambiente, o solvente é absorvido principalmente por inalação. O objetivo do estudo é avaliar a influência da exposição inalatória ao tolueno na atividade in vivo do polipeptídeo transportador de ânions orgânicos da família Oatp em ratos, empregando como fármaco marcador a pravastatina. Ratos machos Wistar (n=6 por tempo de coleta, por grupo) foram expostos ao tolueno (85 mg/m3) por inalação ou ao ar em câmara de exposição apenas pelo nariz por 6 horas/dia, 5 dias/semana, 4 semanas. Ao final do período de exposição, os animais receberam dose única de pravastatina (20 mg/kg) por via oral. Amostras seriadas de sangue foram coletadas até 8 horas após a administração de pravastatina. As concentrações plasmáticas do fármaco foram avaliadas por cromatografia líquida de alta eficiência com detecção por espectrometria de massas (LC-MS). O método de análise da pravastatina por LC-MS mostrou detectabilidade, precisão e exatidão compatíveis com a aplicação em estudos de disposição cinética após dose única em ratos. As áreas sob as curvas de concentração plasmática versus tempo (ASC) foram calculadas do tempo zero a infinito com base na Quadratura de Gauss-Laguerre. As concentrações de pravastatina correspondentes aos tempos avaliadas foram estimadas por interpolação polinomial. O clearance total aparente (CL/F) foi calculado a partir da equação: CL/F = dose/ASC0-∞. Na avaliação da disposição cinética da pravastatina, os animais não expostos ao tolueno apresentaram ASC0-∞ de 726 ng h/mL e Cl/F de 49,1 L/h kg. Não houve diferença estatística na ASC0-∞ ao comparar os animais expostos (ASC0-∞: 681,8 ng h/mL) e não expostos ao tolueno. Os resultados do estudo permitem concluir que a atividade de transportadores Oatp, avaliada pelo uso da pravastatina como fármaco marcador, não foi alterada após a exposição ao tolueno por inalação a 85 mg/m3, 6 horas/dia, 5 dias/semana, 4 semanas em ratos.
Occupational exposure to chemical agents is potentially able to modify the kinetic disposition of drug metabolism, mainly due to the induction or inibition of cytochrome P450 enzymes. However, studies investigating the influence of occupational exposure to chemicals on the variability in drug response are rare. Toluene is present in the working environment particularly in vapor form. In this environment, the toluene is mainly absorbed by inhalation. Considering that, the aim of this study was evaluate the influence of inhalation to toluene in the in vivo activity of the polypeptide transporter organic anion (Oatp) family transporters in rats, using pravastatin as a probe drug. Male Wistar rats (n=6, for each sampling time) were exposed to toluene (85 mg / m3) by inhalation or air in a nose only exposure system for 6 hours/day, 5 days/week, during 4 weeks. After 4 weeks of exposure, animals received a single dose of pravastatin (20 mg/kg) orally. Serial blood samples were collected up to 8 hours after administration of pravastatin. Plasma concentrations of pravastatin were measured by high-performance liquid chromatography with detection by mass spectrometry (LC-MS). The analysis method of pravastatin by LC-MS showed detectability, precision and accuracy compatible with the application in kinetic disposition studies after single doses in rats. The areas under the plasma concentration versus time (AUC) were calculated by zero to the infinity by the Gauss-Laguerre Quadrature. The concentrations corresponding to the times were estimated by polynomial interpolation. The total clearance apparent (CL/F) was calculated from the equation: CL/F = dose/AUC0-∞. In assessing the kinetics of pravastatin disposition, animals not exposed to toluene showed AUC0-∞ of 726 ng h/mL and CL/F of 49.1 L/h kg. There was no statistical difference in AUC0-∞ to compare the exposed animals (AUC0-∞: 681.8 ng h/mL) and not exposed to toluene. The results of this study showed that Oatp family transporters activity, assessed by the use of pravastatin as a marker drug, was not altered after exposure to toluene by inhalation at 85 mg/m3 6 hours/day, 5 days/week and for 4 weeks in rats.
Occupational exposure to chemical agents is potentially able to modify the kinetic disposition of drug metabolism, mainly due to the induction or inibition of cytochrome P450 enzymes. However, studies investigating the influence of occupational exposure to chemicals on the variability in drug response are rare. Toluene is present in the working environment particularly in vapor form. In this environment, the toluene is mainly absorbed by inhalation. Considering that, the aim of this study was evaluate the influence of inhalation to toluene in the in vivo activity of the polypeptide transporter organic anion (Oatp) family transporters in rats, using pravastatin as a probe drug. Male Wistar rats (n=6, for each sampling time) were exposed to toluene (85 mg / m3) by inhalation or air in a nose only exposure system for 6 hours/day, 5 days/week, during 4 weeks. After 4 weeks of exposure, animals received a single dose of pravastatin (20 mg/kg) orally. Serial blood samples were collected up to 8 hours after administration of pravastatin. Plasma concentrations of pravastatin were measured by high-performance liquid chromatography with detection by mass spectrometry (LC-MS). The analysis method of pravastatin by LC-MS showed detectability, precision and accuracy compatible with the application in kinetic disposition studies after single doses in rats. The areas under the plasma concentration versus time (AUC) were calculated by zero to the infinity by the Gauss-Laguerre Quadrature. The concentrations corresponding to the times were estimated by polynomial interpolation. The total clearance apparent (CL/F) was calculated from the equation: CL/F = dose/AUC0-∞. In assessing the kinetics of pravastatin disposition, animals not exposed to toluene showed AUC0-∞ of 726 ng h/mL and CL/F of 49.1 L/h kg. There was no statistical difference in AUC0-∞ to compare the exposed animals (AUC0-∞: 681.8 ng h/mL) and not exposed to toluene. The results of this study showed that Oatp family transporters activity, assessed by the use of pravastatin as a marker drug, was not altered after exposure to toluene by inhalation at 85 mg/m3 6 hours/day, 5 days/week and for 4 weeks in rats.
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Palavras-chave
Tolueno, Transportadores da família Oatp, Pravastatina, Farmacocinética, Toluene, Oatp family transporters, Pravastatin, Pharmacokinetics