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      Development of a Versatile Laboratory Experiment to Teach the Metabolic Transformation of Hydrolysis

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          Abstract

          In this paper we describe an easy, reliable, versatile and inexpensive laboratory experiment to teach the metabolic transformation of hydrolysis to Pharmacy students. The experiment does not require the sacrifice of any experimental animal, or any work with organs or tissues, and so can be implemented in a typical university chemistry laboratory. We used acetylsalicylic acid (ASA), hexyl salicylate (HS) and two enzymes, a lipase and an esterase. Since both ASS and HS liberate salicylic acid (SA) upon hydrolysis, students can evaluate the different enzymatic transformations by monitoring the amount of SA liberated. The learning outcomes are an enhanced student understanding of: (1) the process of hydrolysis; (2) the application of enzymatic transformations of molecules from food to xenobiotics; (3) the differences between the general specificity of substrate of both enzymes; (4) the concepts of the lipophilic pocket; (5) the catalytic triad and its regioselectivity in relation to the ester bond. A questionnaire was administered to participating students at three points in time: at the beginning of the module, after enzymatic hydrolysis was taught in class, and after the laboratory experiment. From an analysis of the questionnaire data we conclude that this practical helped Pharmacy students to understand these concepts.

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          Most cited references 19

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          Prodrugs: design and clinical applications.

          Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.
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            Grapefruit juice-drug interactions.

            The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
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              Drug interactions due to cytochrome P450.

               C Ogu,  J Maxa (2000)
              Cytochrome P450 is a family of isozymes responsible for the biotransformation of several drugs. Drug metabolism via the cytochrome P450 system has emerged as an important determinant in the occurrence of several drug interactions that can result in drug toxicities, reduced pharmacological effect, and adverse drug reactions. Recognizing whether the drugs involved act as enzyme substrates, inducers, or inhibitors can prevent clinically significant interactions from occurring. Avoiding coadministration or anticipating potential problems and adjusting a patient's drug regimen early in the course of therapy can provide optimal response with minimal adverse effects.
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                Author and article information

                Journal
                BJPharm
                British Journal of Pharmacy
                University of Huddersfield Press
                2058-8356
                14 November 2016
                : 1
                : 1
                : 106-114
                Affiliations
                [1 ]Department of Pharmacy, School of Applied Sciences and Pharmacy, University of Huddersfield, HD1 3DH, UK
                [2 ]Qualitas Research, Marsden, Huddersfield, HD7 6EL, UK
                [3 ]Department of Pharmacy and Chemistry, School of Life Sciences, Kingston University, Surrey, UK
                Author notes
                *Corresponding author. Tel.: +44 1484845153 E-mail: jordim69@ 123456yahoo.com
                Article
                10.5920/bjpharm.2016.12
                © 2016, Antonella Campanile, Kim Morral, Mohammad Khaled Aljammal, Felix Owsu-Kwarteng, Elena Tillotson, Mohammed Shabbir, Ian Beadham, Jordi Morral

                This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY) 4.0 https://creativecommons.org/licenses/by/4.0/.

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