Abstract
This chapter summarizes the pharmacokinetic drug interactions of select opioid agents, focusing on underlying molecular mechanisms (e.g., known metabolic interactions at the enzymatic and transporter levels, such as cytochrome P450 [CYP450], uridine 5’-diphospho-glucuronosyltransferases [UGT], and drug transporters) and drawing a connection to pharmacodynamic interactions in clinical studies. The majority of data has focused on drug metabolism, and there are in vitro data to support the in vivo observations. Many opioids (e.g., codeine) are metabolized by enzymes that are known to exhibit genetic polymorphism, and this additional (gene-drug interaction) factor must be considered. Most data on opioids have focused on their classical analgesic properties, effects on pain threshold, and adverse effects such as somnolence, nausea/vomiting, gastrointestinal motility, or miosis. Additional atypical adverse effects such QTC prolongation (e.g., associated with methadone) or serotonin syndrome (e.g., associated with tramadol) must be considered and can be manifested by pharmacokinetic-associated pharmacodynamic interactions. Information on pharmacokinetic-mediated pharmacodynamic interactions is relatively scarce in the literature compared to the available pharmacokinetic data. The available human data for opioids only represent a small fraction of all the possible drug interactions but one may use various in vitro or in silico approaches to aid the prediction of pharmacokinetic interactions. Evidence that a significant pharmacokinetic interaction is associated with a pharmacodynamic interaction must be appropriately weighted based on limitations in the design of existing studies. This chapter concludes with a proposed clinical decision-making algorithm that may be used to ascertain the clinical significance of pharmacokinetic-mediated pharmacodynamic interactions with opioid analgesics:
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Kiang TK, Wilby KJ, Ensom MHH (2015) Clinical Pharmacokinetic and pharmacodynamic drug interactions associated with antimalarials. Springer International Publishing, Switzerland. ISBN 978-3-319-10526-0
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Kiang, T.K.L., Ensom, M.H.H. (2016). Clinical Significant Interactions with Opioid Analgesics. In: Jann, M., Penzak, S., Cohen, L. (eds) Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents. Adis, Cham. https://doi.org/10.1007/978-3-319-27883-4_20
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