title: Methotrexate-bestatin interaction: involvement of P-glycoprotein and organic anion transporters in rats.
abstract: 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.
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: zhuyanna.1986@163.com.
authors: Yanna
authors: Y
authors: Zhu
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: mengq531@yahoo.cn.
authors: Qiang
authors: Q
authors: Meng
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: wangcyuan@163.com.
authors: Changyuan
authors: C
authors: Wang
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: llaqii@yahoo.com.cn.
authors: Qi
authors: Q
authors: Liu
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: huoxiaokui@163.com.
authors: Xiaokui
authors: X
authors: Huo
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China. Electronic address: Zhangaijie1986@163.com.
authors: Aijie
authors: A
authors: Zhang
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: spfar1004@gmail.com.
authors: Pengyuan
authors: P
authors: Sun
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: sunhuijun@hotmail.com.
authors: Huijun
authors: H
authors: Sun
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: dllihua@126.com.
authors: Hua
authors: H
authors: Li
authors: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China; Research Institute of Integrated Traditional and Western Medicine of Dalian Medical University, Dalian, China; Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, China. Electronic address: kexinliu@dlmedu.edu.cn.
authors: Kexin
authors: K
authors: Liu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D020014:K562 Cells; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007930:Leucine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D027361:Organic Anion Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D065608:Renal Reabsorption / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027361:Organic Anion Transporters; D007930:Leucine; C012211:ubenimex; D008727:Methotrexate
keywords: Bestatin; Drug–drug interaction; Methotrexate; Organic anion transporter; P-glycoprotein