Please cite this article in press as: Varum, F.J.O., et al., Food, physiology and drug delivery. Int J Pharmaceut (2013), http://dx.doi.org/10.1016/j.ijpharm.2013.04.034 ARTICLE IN PRESS G Model IJP 13276 1–15 International Journal of Pharmaceutics xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect International Journal of Pharmaceutics j o ur nal ho me page: www.elsevier.com/locate/ijpharm Food, physiology and drug delivery F.J.O. Varum 1 , G.B. Hatton, A.W. Basit ∗ Q1 Department of Pharmaceutics, UCL School of Pharmacy, University College London, WC1N 1AX, London, UK a r t i c l e i n f o Article history: Received 17 December 2012 Received in revised form 8 April 2013 Accepted 12 April 2013 Available online xxx Keywords: Meal effects Q2 Alcohol effects Pharmacokinetics Dose dumping Controlled release Delayed release Colonic drug delivery Enteric coatings Gastrointestinal transit Gamma scintigraphy Biorelevant dissolution testing a b s t r a c t Gastrointestinal physiology is dynamic and complex at the best of times, and a multitude of known vari- ables can affect the overall bioavailability of drugs delivered via the oral route. Yet while the influences of food and beverages, including alcohol, intake as just two of these variables on oral drug delivery have been extensively documented in the wider literature, specific information on their effects remains spo- radic, and is not so much contextually reviewed. Food co-ingestion with oral dosage forms can mediate several changes to drug bioavailability, yet the precise mechanisms underlying this have yet to be fully elucidated. Likewise, alcohol (ethanol) effects on drug delivery have been observed experimentally and clinically, and often to the detriment of dosage form performance. Here, we attempt to piece together the available subject matter relating to effects mediated by both solid and liquid foodstuffs on the gastroin- testinal milieu and the implications for oral drug delivery, with particular emphasis on the behaviour of modified-release dosage forms, formulation robustness and drug absorption. Providing better insight into these influences and exemplifying cases where formulations have been developed or modified to circumvent their associated problems can help to appropriately direct the design of better in vitro diges- tive modelling systems and future oral dosage forms resilient to these effects. Moreover, it will expand on our understanding of the impact of food and alcohol intake on normal gut behaviour/function. © 2013 Published by Elsevier B.V. 1. Introduction Presently, peroral administration largely remains the most con- venient and popular means of providing both immediate and modified release of drugs. This means of administering drugs often occurs under conditions of meal intake, and usually several times a day. The knowledge of the effects of foods and fluids on the perfor- mance of oral formulations, including modified-release systems, and on drug pharmacokinetics is crucial to our continued under- standing of factors influencing oral bioavailability, and can be of particular relevance to the often poly-medicated geriatric popula- tion. Indeed, the concomitant administration of oral dosage forms with food has the potential to affect oral drug bioavailability, sup- plementary to parameters including lag time, rate and extent of absorption (Fleisher et al., 1999; Yasuji et al., 2012), and is an issue which has gained increased attention in recent years; posing sev- eral challenges to the design of drugs from developmental, clinical and regulatory perspectives. Often regarded as physical barriers inasmuch as physicochemical ones, the complexity of food effects ∗ Corresponding author. Tel.: +44 20 7753 5865; fax: +44 20 7753 5865. E-mail addresses: abdul.basit@pharmacy.ac.uk, a.basit@ucl.ac.uk (A.W. Basit). 1 Present address: Tillotts Pharma AG, Baslerstrasse 15, CH-4310 Rheinfelden, Switzerland. on the oral drug bioavailability results from the dynamic interplay between the changing physiological environment of the fed gut, the physicochemical properties of the drug, drug dosing, and the characteristics of the formulations. Food-mediated effects on oral drug bioavailability are already well described and reviewed in the literature (Fleisher et al., 1999; Schmidt and Dalhoff, 2002; Singh and Malhotra, 2004; Yasuji et al., 2012), and it is not our intention to revisit these issues in great detail. Briefly, a food–drug interaction can lead to five main differ- ent outcomes (Welling, 1996): • No effect on oral bioavailability; • Positive food effect and consequent increase in bioavailability, potentially compromising safety; • Negative food effect and consequent decrease in bioavailability, potentially compromising efficacy; • Delayed absorption; • Accelerated absorption. Particularly relevant to potential food effects are the phys- icochemical characteristics of drugs, to which end both the Biopharmaceutical Classification System (BCS) and the Biophar- maceutical Drug Disposition Classification System (BDDCS) – categorizing drugs according to their solubility, permeability and metabolism – have contributed to the creation of a framework used in predicting these effects (Amidon et al., 1995; Wu and Benet, 0378-5173/$ – see front matter © 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ijpharm.2013.04.034 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66