RESUMO
AIM: Furosemide is a loop diuretic. Different authors demonstrated that continuous administration of furosemide modulates the expression of organic anion transporters. This study was undertaken to simultaneously evaluate the effects of furosemide pretreatment on organic anion transporter 1 (Oat1) and multidrug resistance protein 2 (Mrp2) renal expressions, on p-aminohippurate (PAH) pharmacokinetics and on renal and urinary PAH levels in rats. METHODS: Male Wistar rats were treated with furosemide (6 mg/100 g body weight per day, subcutaneously, 4 days) (treated group) or saline (control group). On the fifth day, PAH was administered as a bolus infusion in the femoral vein, and plasma samples were obtained from femoral artery at different time points. PAH levels in renal tissue and urine were also assessed. Renal Oat1 and Mrp2 expressions were evaluated by western blotting. RESULTS: Furosemide pretreatment increased both the expression of Oat1 and Mrp2. PAH plasma concentrations decreased following a biexponential function. The furosemide-treated group showed higher PAH plasma levels, a lower systemic clearance and elimination rate constant from the peripheral compartment, indicating that PAH renal elimination was decreased. PAH levels in renal tissue were significantly elevated and in urine appeared to be significantly lower as compared with control animals. CONCLUSIONS: Furosemide pretreatment caused a significant decrease of PAH renal elimination, despite Oat1 and Mrp2 augmented renal expression. The goal of the present study is the addition of important information in the wide gap of knowledge that exists about drug-drug interactions. Because of furosemide worldwide use, the data obtained are interesting and useful in terms of translation to clinical practice.
Assuntos
Furosemida/farmacologia , Rim/efeitos dos fármacos , Proteína 1 Transportadora de Ânions Orgânicos/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Ácido p-Aminoipúrico/farmacocinética , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Interações Medicamentosas , Furosemida/administração & dosagem , Injeções Intravenosas , Injeções Subcutâneas , Rim/metabolismo , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Ratos Wistar , Eliminação Renal/efeitos dos fármacos , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Regulação para Cima , Ácido p-Aminoipúrico/administração & dosagem , Ácido p-Aminoipúrico/sangue , Ácido p-Aminoipúrico/urinaRESUMO
Pharmacokinetic studies of the drugs administered to subjects with mechanical cholestasis are scarce. The purpose of the present study was to examine the effects of bile duct ligation of 3 days (peak of elevation of serum bile acids and bilirubin) on the systemic and renal PAH clearance and on the expression of cortical renal OAT1 and OAT3 in a rat model. PAH is the prototypical substrate of the renal organic anion transport system. Male Wistar rats underwent a bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. BDL rats displayed a significantly lower systemic PAH clearance. Renal studies revealed a reduction in the renal clearance and in the excreted and secreted load of PAH in BDL rats. The OAT1 protein expression in kidney homogenates was not modified, but it decreased in the basolateral membranes from BDL rats. In contrast, OAT3 abundance in both kidney cortex homogenates and in basolateral membranes increased by 3 days after the ligation. Immunocytochemical studies (light microscopic and confocal immunofluorescence microscopic analyses) confirmed the changes in the renal expression of these transport proteins. The present study demonstrates the key role of OAT1 expression in the impaired elimination of PAH after 3 days of obstructive cholestasis.
Assuntos
Colestase/urina , Rim/fisiopatologia , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ácido p-Aminoipúrico/urina , Animais , Ductos Biliares/fisiologia , Proteínas Sanguíneas/metabolismo , Membrana Celular/metabolismo , Colestase/sangue , Córtex Renal/metabolismo , Cinética , Masculino , Taxa de Depuração Metabólica , Ratos , Ratos Wistar , Ácido p-Aminoipúrico/sangue , Ácido p-Aminoipúrico/farmacocinéticaRESUMO
The importance of considering sex differences in drug handling studies was admitted recently. The present work evaluates the sex influences on the pharmacokinetics of para-aminohippuric acid (PAH), the reference substance for the renal organic anion transports systems, and furosemide (FS), a standard loop diuretic which is also a substrate for this transport system. Female rats displayed a lower PAH and FS systemic clearance, and a lower value of the elimination rate microconstant from the central compartment for both drugs. These results may be explained by the diminution of the renal clearance of both PAH and FS observed in females. In summary, sex modifies the pharmacokinetics of organic anions. Although additional experimental work must be done to bridge the gap between studies using animals and humans, the reported experimental observations may have potentially important pharmacological implications. So, caution must be exercised in administering drugs like organic anions to females.
Assuntos
Furosemida/farmacocinética , Rim/metabolismo , Ácido p-Aminoipúrico/farmacocinética , Animais , Ânions , Transporte Biológico , Feminino , Furosemida/sangue , Furosemida/urina , Masculino , Ratos , Ratos Wistar , Fatores Sexuais , Ácido p-Aminoipúrico/sangue , Ácido p-Aminoipúrico/urinaRESUMO
Gender differences in the renal handling on drugs and toxins have received too little attention. In the present study, a variety of preparations were used to examine the basis for the greater effectiveness of the male kidneys in the elimination of p-aminohippurate (PAH) in rats. Renal clearance of PAH was significantly lower in female rats as consequence of its smaller filtered and secreted load. The gender difference in the filtered load may be accounted for the lower value of glomerular filtration rate (GFR) displayed by female rats as compared with males. The lower value of the renal blood flow observed in females might explain, at least in part, the decrease in the GFR and in the secreted load of PAH. In females, maximal uptake for PAH transport into renal basolateral membrane vesicles decreased to 52+/-9% (P < 0.05) and Michaelis-Menten constant for PAH uptake into renal brush border membrane vesicles was increased to 163+/-8% (P < 0.05). These changes might also explain the lower secreted load of PAH. The sex difference in the renal clearance of PAH was also evidenced by the reduced systemic clearance observed in female rats.
Assuntos
Córtex Renal/metabolismo , Ácido p-Aminoipúrico/farmacocinética , Animais , Feminino , Taxa de Filtração Glomerular , Testes de Função Renal , Masculino , Taxa de Depuração Metabólica , Microvilosidades/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Ácido p-Aminoipúrico/sangue , Ácido p-Aminoipúrico/urinaRESUMO
This study was designed to investigate the role of lipid peroxidation in the pathogenesis of renal dysfunction in glutathione (GSH)-depleted rats. Renal function parameters and acid-base status were analyzed in diethylmaleate (DEM)-treated rats previously injected with vitamin E (Vit.E). Vit.E was effective in inhibiting the elevation in renal lipid peroxidation found in GSH-depleted rats. Vit.E also ameliorated the renal response to the metabolic acidosis without modification in lactate production induced by DEM administration. The increase in sodium and water urine excretion and the diminution of the urine to plasma osmolalities ratio were not reversed in these animals. These results lead us to conclude that lipid peroxidation is associated with distal acidification impairment observed with GSH-depletion, but it is not related to the sodium reabsorption alteration in the ascending loop of Henle.
Assuntos
Glutationa/deficiência , Rim/metabolismo , Peroxidação de Lipídeos/fisiologia , Vitamina E/farmacologia , Equilíbrio Ácido-Base , Animais , Rim/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Maleatos/farmacologia , Ratos , Ratos Endogâmicos , Ácido p-Aminoipúrico/sangue , Ácido p-Aminoipúrico/urinaRESUMO
Fenoldopam administration orally or i.v. resulted in significant increases in paraaminohippuric acid (PAH) clearance in both four control dogs and four dogs with chronic renal failure. Oral fenoldopam resulted in significant plasma levels of fenoldopam sulfate metabolites. One metabolite, fenoldopam-8-sulfate, a potential inhibitor of organic anion transport, did not depress renal cortical slice accumulation of PAH. The data therefore indicate that in dogs with chronic renal failure, PAH clearance after fenoldopam administration is a reliable measure of renal plasma flow, and fenoldopam can result in an increase in renal plasma flow.