Polysorbate 20 increases oral absorption of digoxin in wild-type Sprague Dawley rats, but not in mdr1a(-/-) Sprague Dawley rats

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• 作者：Carsten Uhd Nielsen^a ; ^{cun@sdu.dk" class="auth_mail" title="E-mail the corresponding author} ; Ahmed A. Abdulhussein^a ; Dilan Colak^b ; René ; Holm^c ; ¹
• 关键词：Digoxin ; P-gp ; Polysorbate ; mdr1a(-/-) Sprague Dawley rats ; MDCKII-MDR1 cells ; Caco-2 cells
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：20 November 2016
• 年：2016
• 卷：513
• 期：1-2
• 页码：78-87
• 全文大小：1164 K

文摘

The aim was to investigate the ability of polysorbate 20 to alter oral digoxin absorption in vitro and drug exposure in vivo via modulation of transporter mediated efflux. Transport studies were performed in MDCKII-MDR1 and Caco-2 cells using ³H-digoxin. Pharmacokinetic studies were performed in wild type and mdr1a deficient Sprague Dawley rats. ³H-digoxin was quantified using liquid scintillation counting. The results showed an increased absorptive transport and a reduced secretory transport in MDCKII-MDR and Caco-2 cells as a function of polysorbate 20 concentrations. The secretory transport (B–A) of digoxin was reduced by 50% at lower polysorbate 20 concentrations than required to increase the absorptive transport (A-B). In vivo, the oral bioavailability of digoxin in wild type animal was increased by 10–25% (w/v) polysorbate 20. In mdr1a deficient Sprague Dawley rats 25% (w/v) polysorbate 20 did not alter the absorption of digoxin after oral administration, but digoxin exposure was significantly different between wild type and mdr1a deficient rats. In conclusion, polysorbate 20 increased absorptive transport across Caco-2 cell monolayers and in vivo in rats in a concentration dependent manner, most likely via inhibition of P-gp rather than through solubilization of digoxin.