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. 2018 Sep 6;10(3):152.
doi: 10.3390/pharmaceutics10030152.

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  4 , Jun Young Lim  5 , Hyeon Myeong Jeong  6 , Chang Ho Song  7 , Youn-Woong Choi  8 , Sang-Min Cho  9 , Kyu-Yeol Nam  10 , Won-Ho Kang  11 , Soyoung Shin  12 , Beom Soo Shin  13
Affiliations

Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats

Tae Hwan Kim et al. Pharmaceutics. .

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; gastric ulcer; pharmacokinetics.

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Conflict of interest statement

The authors declare no conflict of interest. Y.-W.C., S.-M.C., K.-Y.N., and W.-H.K. are full-time employees of Korea United Pharm. Inc. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Aceclofenac (ACE) 200 mg/kg-induced gastric ulcers represented by (A) ulcer index, (B) ulcer area (mm2), and (C) relative ulcer area (%) in the absence or in the presence of pre-treatments with esomeprazole (ESO) 0, 5, 10, 20, 40 mg/kg in rats. Each column represents the mean ± SD. *, p < 0.05 vs. control (ACE = 0/ESO = 0 mg/kg); #, p < 0.05 vs. ACE = 200/ESO = 0 mg/kg.
Figure 2
Figure 2
Average plasma concentration-time profiles of (A) aceclofenac, (B) diclofenac, and (C) esomeprazole following oral administration of aceclofenac (20 mg/kg) in combination with esomeprazole (0, 4, 8 mg/kg) in rats. Data represent mean ± SD (n = 4–6).
Figure 3
Figure 3
Average plasma concentration-time profiles of (A) aceclofenac, (B) diclofenac, and (C) esomeprazole following oral administration of vehicle A, B, C, and D containing aceclofenac (20 mg/kg for A, B, and C and 200 mg/kg for D) and esomeprazole (4 mg/kg for A, B, and C and 20 mg/kg for D) in rats.
Figure 3
Figure 3
Average plasma concentration-time profiles of (A) aceclofenac, (B) diclofenac, and (C) esomeprazole following oral administration of vehicle A, B, C, and D containing aceclofenac (20 mg/kg for A, B, and C and 200 mg/kg for D) and esomeprazole (4 mg/kg for A, B, and C and 20 mg/kg for D) in rats.
Figure 4
Figure 4
Average plasma concentration-time profiles of (A) aceclofenac, (B) diclofenac, and (C) esomeprazole following oral administration of aceclofenac (20 mg/kg) in combination with esomeprazole (4 mg/kg) in rats with fasting vs. fed conditions. Data represent mean ± SD (n = 4–5).
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