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Molecules 2017, 22(9), 1488;

Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL 32827, USA
College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Korea
College of Pharmacy, Catholic University of Daegu, 13-13 Hayang-ro, Hayang-eup, Gyeongsan-si, Gyeongbuk 38430, Korea
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Korea
Department of Rehabilitation Medicine, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea
Tae Hwan Kim and Soyoung Shin contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 9 July 2017 / Revised: 31 August 2017 / Accepted: 5 September 2017 / Published: 7 September 2017
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S-1 (TS-1®) is an oral fluoropyrimidine anticancer agent containing tegafur, oteracil, and gimeracil. Sipjeondaebo-tang (SDT) is a traditional oriental herbal medicine that has potential to alleviate chemotherapy-related adverse effects. The aim of the present study was to evaluate the effect of SDT on the pharmacokinetics of S-1. Sprague-Dawley rats were pretreated with a single dose or repeated doses of SDT for seven consecutive days (1200 mg/kg/day). After the completion of pretreatment with SDT, S-1 was orally administered and plasma concentrations of tegafur, its active metabolite 5-FU, and gimeracil were determined by liquid chromatography-tandem mass spectrometry (LC/MS/MS). A population pharmacokinetic model was developed to evaluate the effect of SDT on pharmacokinetics of tegafur and 5-FU. Although a single dose of SDT did not have any significant effect, the absorption rate of tegafur decreased, and the plasma levels of 5-FU reduced significantly in rats pretreated with SDT for seven days in parallel to the decreased gimeracil concentrations. Population pharmacokinetic modeling also showed the enhanced elimination of 5-FU in the SDT-pretreated group. Repeated doses of SDT may inhibit the absorption of gimeracil, an inhibitor of 5-FU metabolism, resulting in enhanced elimination of 5-FU and decrease its plasma level. View Full-Text
Keywords: herbal medicine; drug-drug interaction; pharmacokinetics; 5-FU; gimeracil; Sipjeondaebo-tang herbal medicine; drug-drug interaction; pharmacokinetics; 5-FU; gimeracil; Sipjeondaebo-tang

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Kim, T.H.; Shin, S.; Shin, J.C.; Bulitta, J.B.; Weon, K.-Y.; Yoo, S.D.; Park, G.-Y.; Jeong, S.W.; Kwon, D.R.; Min, B.S.; Woo, M.H.; Shin, B.S. Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling. Molecules 2017, 22, 1488.

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