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Insight Into the Colonic Disposition of Celecoxib in Humans

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Insight Into the Colonic Disposition of Celecoxib in Humans European Journal of Pharmaceutical Sciences 145 (2020) 105242 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Insight into the colonic disposition of celecoxib in humans T ⁎ Glenn Lemmensa,1, Joachim Brouwersa,1, Jan Snoeysb, Patrick Augustijnsa, , Tim Vanuytselc a Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 – box 921, 3000, Leuven, Belgium b Drug Metabolism and Pharmacokinetics, Janssen R&D, Turnhoutseweg 30, 2340, Beerse, Belgium c Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, Herestraat 49, 3000 Leuven, Belgium ARTICLE INFO ABSTRACT Keywords: Although the effect of NSAIDs such as celecoxib on the progression of colorectal polyps has been established, itis Colon currently unknown how sufficiently high concentrations of celecoxib are reached in colonic tissue. Indeed,the Oral drug delivery lipophilic and poorly soluble celecoxib is orally dosed as an immediate release capsule without any colon- Disposition targeting delivery strategy. In the present study, we aimed to distinguish between plasma and gut driven caecal Absorption tissue accumulation of celecoxib in healthy volunteers. After developing a protocol to reliably collect colonic Celecoxib biopsies and contents, the disposition of celecoxib was assessed in plasma, caecal tissue and caecal contents Low solubility ® Clinical study collected after intake of a celecoxib capsule (200 mg; Celebrex ) with 240 mL of tap water. During a first Biopharmaceutics colonoscopy (1.0–2.5 h after drug intake), plasma concentrations of celecoxib and its carboxy metabolite were increasing, while caecal tissue concentrations were relatively low. As no celecoxib was present in caecal con- tents, tissue accumulation was clearly plasma driven. During a second colonoscopy (6.0–7.5 h after drug intake), tissue concentrations of the drug and its metabolite were substantially higher despite decreasing plasma con- centrations. As a high amount of celecoxib was found in the caecal contents, the increased tissue accumulation most likely resulted from direct uptake of celecoxib from the gut. These data demonstrate that incomplete small intestinal absorption of the poorly soluble drug celecoxib enables gut driven drug accumulation in caecal tissue, which is, most likely, critical for the role of this NSAID in the prevention of colorectal cancer. 1. Introduction instance, after taking 400 mg of the COX-2 inhibitor celecoxib twice a day for three years, the incidence of recurrent adenomas was reduced Colorectal cancer is the third most abundant type of cancer, with an by 45% (Bertagnolli et al., 2006). Treatment of familial adenomatous estimated 1.8 million new cases in 2018 (Bray et al., 2018). In- polyposis patients with 150 mg sulindac twice a day for 9 months re- flammation plays a key role in the development and progression ofthe duced the number of polyps with 44% and their size with 35% disease; therefore, non-steroidal anti-inflammatory drugs (NSAIDs) (Herendeen and Lindley, 2003). Also for the COX-1 inhibitor aspirin, such as sulindac, aspirin, and celecoxib are eligible candidates for the the Melbourne Control Case Study showed a 42% reduction in the risk treatment and/or prevention of precursor lesions of colorectal cancer; of colorectal cancer (Burn and Sheth, 2016). However, COX-2 inhibitors i.e. polyps. NSAIDs inhibit the cyclooxygenase (COX) pathway, in ad- such as celecoxib are generally preferred over COX-1 inhibitors as up- dition to many COX-independent pathways. In humans, two important regulation of COX-2 happens in the early stages of carcinogenesis, and isoforms of COX exist: COX-1 is expressed constitutively and is im- as they are associated with less severe side effects (Fujimura et al., portant for maintaining the physiological functions of the gastro- 2006). intestinal tract, while COX-2 is an inducible isoform that becomes To exert their effect on colorectal cancer progression, the NSAIDs overexpressed in states of inflammation and carcinogenesis (Gong et al., need to be present at sufficiently high concentrations in the colon. To 2012). The effect of NSAIDs in colorectal cancer treatment andpre- date, however, the disposition of these NSAIDs in the human colon has vention has been reported in several epidemiological studies. For not been evaluated yet. In this respect, it is currently unknown how Abbreviations: COX, cyclooxygenase; CXB, celecoxib; CXB-OH, hydroxy celecoxib; CXB-COOH, carboxy celecoxib; Cmax, maximal drug concentration; IS, internal standard, LC: liquid chromatography; Tmax, time to reach maximal drug concentration ⁎ Corresponding author. E-mail addresses: [email protected] (G. Lemmens), [email protected] (J. Brouwers), [email protected] (J. Snoeys), [email protected] (P. Augustijns), [email protected] (T. Vanuytsel). 1 These authors equally contributed to the manuscript and should be considered as joint first authors https://doi.org/10.1016/j.ejps.2020.105242 Received 4 December 2019; Received in revised form 17 January 2020; Accepted 31 January 2020 Available online 31 January 2020 0928-0987/ © 2020 Elsevier B.V. All rights reserved. G. Lemmens, et al. European Journal of Pharmaceutical Sciences 145 (2020) 105242 these compounds reach the colon. After oral administration, the NSAIDs 2.2. Media are absorbed in the systemic circulation and, as such, distributed across the body, including the colon. However, relatively high concentrations Medium (HBSS+) was prepared by dissolving 25 mM glucose in are needed to demonstrate anti-carcinogenic effects in in vitro cell 500 mL HBSS, buffered with 10 mM HEPES and adjusted to pH 7.4 with cultures. Indeed, Grösch et al. (2006) reported that concentrations of 2 M of NaOH. celecoxib between 10 µM and 100 µM are generally used in cell culture experiments to get anti-carcinogenic effects, which are not reached in 2.3. Clinical studies plasma by administering a single 200 mg dose. Therefore, it can be questioned whether direct uptake from the gut lumen into the colonic 2.3.1. Study medication tissue might be required, even though neither of the NSAIDs have been Celebrex® capsules (200 mg celecoxib; Pfizer, Brussels, Belgium) formulated as a colon-targeting delivery system. In the present study, were ordered via the hospital pharmacy of the University Hospitals we aim to shed light on the colonic disposition of the COX-2 inhibitor Leuven (UZ Leuven, Belgium). celecoxib after oral administration of its dosage form Celebrex® (im- mediate release capsule, 200 mg) 2.3.2. Ethics Celecoxib (CXB) is a lipophilic (LogP = 3.5), and weakly acidic Clinical trials followed the tenets of the Declaration of Helsinki and drug (pKa = 11.1) (Pfizer, 2016). It has been reported as a high per- were approved by the Federal Agency for Medicines and Health meability drug (Paulson et al., 2001), explaining why the compound is Products (FAMHP; EudraCT reference numbers 2017-000131-13, 2017- rapidly absorbed (tmax = 1 h) in dogs when administered orally as a 001194-16) and the Ethics Committee Research UZ/KU Leuven (re- solution. When dosing celecoxib as a solid, however, absorption is de- ference numbers S60240, S60302, S60322). All volunteers provided layed with 1–2 h, which indicates its low solubility in the aqueous written informed consent prior to participation. Volunteers with he- gastrointestinal environment (Paulson et al., 2001). Increasing the or- patitis B/C and/or HIV infection were excluded to guarantee the safety ally administered dose in rats resulted in a higher fraction of celecoxib of the study personnel. Illness at the time of the study, allergy for that could be retrieved in the faeces (Paulson et al., 2000). As celecoxib NSAIDs, medication use, a history of acute/chronic gastrointestinal is extensively metabolized in the human liver by CYP2C9 to form hy- disease(s), (possible) pregnancy, and/or frequent exposure to radiation droxy celecoxib (CXB–OH), which can then be oxidized to carboxy during the previous year were criteria for exclusion. celecoxib (CXB-COOH) by cytosolic alcohol dehydrogenases ADH1 and ADH2 (Gong et al., 2012), the appearance of celecoxib in the faeces 2.3.3. Study protocol implies that this poorly soluble drug does not get completely absorbed In all studies, volunteers were asked to follow a three-day low-fiber in the upper gastrointestinal tract (Paulson et al., 2000). With respect to diet (e.g. white bread or pasta, canned fruit in heavy syrup or juice, no celecoxib's effect on colorectal polyps and cancer, this observation vegetables, clear drinks…) and to eat a last meal at 8 pm on the day further implies that direct uptake of celecoxib from the colonic lumen before the study. To ensure fasted state conditions, volunteers could into the colonic tissue is possible, even though it should be noted that only drink water 12–2 h prior to the colonoscopy. All studies were the low and scattered water content in the colon hinders drug dis- schematically summarized in Fig. 1. solution and that the comparably smaller surface area of the colonic Study 1: Optimizing enema application and collection of colonic contents mucosa makes it less optimal for drug uptake than the small intestinal Upon arrival at the endoscopy unit, the volunteers (aged between mucosa. 23 and 30 years; 2 men and 3 women) were positioned on their left side To evaluate the pharmacokinetic disposition of celecoxib at the and a varying volume of
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