Methotrexate-bestatin interaction: Involvement of P-glycoprotein and organic anion transporters in rats

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• 作者：Yanna Zhu^a ; ^{zhuyanna.1986@163.com" class="auth_mail} ; Qiang Meng^a ; ^c ; ^{mengq531@yahoo.cn" class="auth_mail} ; Changyuan Wang^a ; ^c ; ^{wangcyuan@163.com" class="auth_mail} ; Qi Liu^a ; ^c ; ^{llaqii@yahoo.com.cn" class="auth_mail} ; Xiaokui Huo^a ; ^{huoxiaokui@163.com" class="auth_mail} ; Aijie Zhang^a ; ^{Zhangaijie1986@163.com" class="auth_mail} ; Pengyuan Sun^a ; ^c ; ^{spfar1004@gmail.com" class="auth_mail} ; Huijun Sun^a ; ^c ; ^{sunhuijun@hotmail.com" class="auth_mail} ; Hua Li^a ; ^c ; ^{dllihua@126.com" class="auth_mail} ; Kexin Liu^a ; ^b ; ^c ; ^{kexinliu@dlmedu.edu.cn" class="auth_mail}
• 关键词：MTX ; methotrexate ; DDI ; drug&ndash ; drug interaction ; P-gp ; P-glycoprotein ; OAT ; organic anion transporter ; MRP ; multidrug resistance-associated protein ; BCRP ; breast cancer resistance protein ; OATP ; organic anion transporting polypeptide ; KRB ; Krebs&ndash ; Ringer buffer ; AUC ; area under the plasma concentration&ndash ; time curve ; CLP ; plasma clearance rate ; CLR ; renal clearance rate ; MDR ; multidrug resistance ; K562 ; doxorubicin-sensitive erythroleukemic cells ; K562/ADR ; doxorubicin-resistant eryth
• 刊名：International Journal of Pharmaceutics
• 出版年：25 April, 2014
• 年：2014
• 卷：465
• 期：1-2
• 页码：368-377
• 全文大小：1577 K

文摘

To clarify the pharmacokinetic interaction and its possible mechanism, mutual effects between methotrexate (MTX) and bestatin in oral absorption and renal excretion in rats were examined in vivo and in vitro. A sensitive, quick and high performance method (LC-MS/MS) was used to determine concentrations of MTX and bestatin in biological samples. Plasma concentrations of MTX and bestatin markedly increased following oral and intravenous administration of MTX in combination with bestatin. The cumulative urinary excretion and renal clearance of the two drugs significantly decreased when MTX and bestatin were co-administered intravenously. Uptake of the two drugs in in situ single-pass intestinal perfusion studies and in vitro everted intestinal sac preparations significantly increased when co-administered, while uptake in rat kidney slices and hOAT1- or hOAT3-HEK 293 cells significantly decreased. Transport rates of bestatin and MTX from basolateral-to-apical transepithelial transport in MDR1-MDCK cells significantly decreased following co-administration. Additionally, intracellular concentrations increased, and the efflux transport of the two drugs was inhibited when given together. The IC₅₀ values of MTX and bestatin in K562 and K562/ADR cells decreased when the two were co-administered. These findings indicate that the pharmacokinetic mechanism of interaction between MTX and bestatin occurs through co-transport by P-gp in the intestinal mucosa and OATs within the kidneys.