Assessment of in vivo organ-uptake and in silico prediction of CYP mediated metabolism of DA-Phen,a new dopaminergic agent |
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| Affiliation: | 1. SiSaf Ltd, Innovation Centre, Northern Ireland Science Park, Queen''s Island, Belfast, BT3 9DT, UK;2. Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Via Archirafi 32, 90123, Palermo, Italy;1. Departamento de Química, Universidade Federal de Viçosa, Viçosa, MG, CEP 36570-000, Brazil;2. Instituto de Química, Universidade Federal de Uberlândia, Uberlândia, MG, CEP 39400-902, Brazil;3. Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, CEP 13566-590, Brazil;4. Departamento de Fitopatologia, Universidade Federal de Viçosa, Viçosa, MG, CEP 36570-000, Brazil;1. School of Chemical Engineering, Beijing Institute of Petrochemical Technology, Beijing 102617, China;2. School of Environment & Biology Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China;3. Liaoning University of Petroleum & Chemical Technology, Fushun 113001, China;4. Petrochina Jinxi Petrochemical Company, Jinxi 125001, China;1. Grupo de Materiales y Sistemas Catalíticos, Instituto de Física del Sur, Departamento de Física, Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía Blanca, Argentina;2. Instituto de Química del Sur, Departamento de Química, Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía Blanca, Argentina;1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA |
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| Abstract: | The drug development process strives to predict metabolic fate of a drug candidate, together with its uptake in major organs, whether they act as target, deposit or metabolism sites, to the aim of establish a relationship between the pharmacodynamics and the pharmacokinetics and highlight the potential toxicity of the drug candidate.The present study was aimed at evaluating the in vivo uptake of 2-Amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DA-Phen) − a new dopaminergic neurotransmission modulator, in target and non-target organs of animal subjects and integrating these data with SMARTCyp results, an in silico method that predicts the sites of cytochrome P450-mediated metabolism of drug-like molecules.Wistar rats, subjected to two different behavioural studies in which DA-Phen was intraperitoneally administrated at a dose equal to 0.03 mmol/kg, were sacrificed after the experimental protocols and their major organs were analysed to quantify the drug uptake. The data obtained were integrated with in silico prediction of potential metabolites of DA-Phen using the SmartCYP predictive tool.DA-Phen reached quantitatively the Central Nervous System and the results showed that the amide bond of the DA-Phen is scarcely hydrolysed as it was found intact in analyzed organs. As a consequence, it is possible to assume that DA-Phen acts as dopaminergic modulator per se and not as a Dopamine prodrug, thus avoiding peripheral release and toxic side effects due to the endogenous neurotransmitter.Furthermore the identification of potential metabolites related to biotransformation of the drug candidate leads to a more careful evaluation of the appropriate route of administration for future intended therapeutic aims and potential translation into clinical studies. |
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| Keywords: | Brain homogenate analysis Organ uptake Da-Phen SMARTCyp prediction |
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