RESUMO
PURPOSE: To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case of prolonged exposure to radioactive iodine. METHODS: The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters. RESULTS: A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KI between 174 and 1190 µg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showed that the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decrease in iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses. CONCLUSION: Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.
Assuntos
Radioisótopos do Iodo/efeitos adversos , Radioisótopos do Iodo/farmacocinética , Iodeto de Potássio/uso terapêutico , Substâncias Protetoras/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Administração Oral , Animais , Radioisótopos do Iodo/sangue , Masculino , Modelos Biológicos , Permeabilidade/efeitos dos fármacos , Iodeto de Potássio/administração & dosagem , Profilaxia Pré-Exposição , Substâncias Protetoras/administração & dosagem , Ratos , Ratos WistarRESUMO
The coadministration of methotrexate (MTX) and proton pump inhibitors (PPIs) can result in a pharmacokinetic interaction that delays MTX elimination and subsequently increases the MTX blood concentrations. Human organic anion transporters (hOATs) are responsible for the renal tubular secretion of MTX and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, which are the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems that express the uptake transporters human embryonic kidney (HEK)-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole, and pantoprazole on OAT-mediated [(3)H]estrone sulfate (ES), [(3)H]p-aminohippuric acid (PAH), and [(3)H]MTX uptake in vitro. hOAT3 is a high affinity transporter for MTX (Km = 21.17 ± 5.65 µM). Omeprazole, lansoprazole, and pantoprazole inhibited [(3)H]MTX uptake in HEK-hOAT3 cells with an IC50 of 6.8 ± 1.16, 1.14 ± 0.26, and 4.45 ± 1.62 µM, respectively, and inhibited the [(3)H]ES uptake in HEK-hOAT3 cells with an IC50 of 20.59 ± 4.07, 3.96 ± 0.96, and 7.89 ± 2.31 µM, respectively. Furthermore, omeprazole, lansoprazole, and pantoprazole exhibited inhibited PAH uptake on hOAT1 in a concentration-dependent manner (IC50 = 4.32 ± 1.26, 7.58 ± 1.06, and 63.21 ± 4.74 µM, respectively). These in vitro results suggest that PPIs inhibit [(3)H]MTX transport via hOAT3 inhibition, which most likely explains the drug-drug interactions between MTX and PPIs and should be considered for other OATs substrates.