pharmaceutics Article Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats Tae Hwan Kim 1 , Subindra Kazi Thapa 2 , Da Young Lee 3 , Seung Eun Chung 3 , Jun Young Lim 3 , Hyeon Myeong Jeong 3 , Chang Ho Song 3 , Youn-Woong Choi 4 , Sang-Min Cho 4 , Kyu-Yeol Nam 4 , Won-Ho Kang 4 , Soyoung Shin 2 and Beom Soo Shin 3, * 1 College of Pharmacy, Catholic University of Daegu, Gyeongsan, Gyeongbuk 38430, Korea; thkim@cu.ac.kr 2 College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 54538, Korea; thapasubindra@gmail.com (S.K.T.); shins@wku.ac.kr (S.S.) 3 School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi 16419, Korea; dayoung717@skku.edu (D.Y.L.); jsehome08@skku.edu (S.E.C.); panacea89@skku.edu (J.Y.L.); wise219143@skku.edu (H.M.J.); sky84312@skku.edu (C.H.S.) 4 Korea United Pharm. Inc., Seoul 06116, Korea; choi0528@kup.co.kr (Y.-W.C.); sweety1723@kup.co.kr (S.-M.C.); kynam@kup.co.kr (K.-Y.N.); kangwonho@kup.co.kr (W.-H.K.) * Correspondence: bsshin@skku.edu; Tel.: +82-31-290-7705 Received: 13 August 2018; Accepted: 4 September 2018; Published: 6 September 2018   Abstract: This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated. Keywords: aceclofenac; diclofenac; esomeprazole; pharmacokinetics; gastric ulcer 1. Introduction Aceclofenac is one of the most popular oral nonsteroidal anti-inflammatory drugs (NSAIDs), and has proven effective in the treatment of osteoarthritis [1], rheumatoid arthritis [2], ankylosing spondylitis [3], and pain [4,5]. The absolute oral bioavailability of aceclofenac is 15% in rats [6] due to extensive metabolism. However, metabolism of aceclofenac is species-specific [7]. While aceclofenac is mainly metabolized to 4 ′ -hydroxyaceclofenac in humans, the major metabolite in rats is diclofenac [7]. Aceclofenac and its metabolites exert anti-inflammatory effects by inhibition of prostaglandin E2 (PGE2) production via cyclooxygenases COX-1 and COX-2. Aceclofenac and 4 ′ -hydroxyaceclofenac are selective Pharmaceutics 2018, 10, 152; doi:10.3390/pharmaceutics10030152 www.mdpi.com/journal/pharmaceutics