Abstract
In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity. This type of inhibition can cause interactions with drugs such as omeprazole, paroxetine, macrolide antibiotics, or mirabegron. A good understanding of mechanism-based inhibition and proper clinical management is needed by clinicians when such drugs are prescribed. It is important to recognize mechanism-based inhibition since it cannot be prevented by separating the time of administration of the interacting drugs. Here, we provide a comprehensive overview of the different types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might affect prescribing and clinical behaviors.
Highlights
In clinical practice, the need for the use of multiple drugs is common, as patients often present with numerous chronic diseases
Basic Concepts of Enzyme, Substrate, and Inhibitor For clarity, as we address the various types of drug metabolism inhibition, the concepts of active (or(tohrothsFtoeosrtrieccr)liacar)niatdyn,daalsalolwlsotesetareidrcidcsrisetiestsse,sth,suseubvbsastrrtiraoatuteesss,t,yaapnneddsioinnfhhdiibrbuiittgoormrssennteaeebedodltitosomffiirirsnsthtbibbeeirterioevnvie,iewthweedecd.o.ncepts of active
Drug interactions due to drug metabolism inhibition are frequent since (1) CYP450-mediated metabolism is the major route of elimination for a large number of drugs, and (2) multiple drugs can compete for the same CYP450 active site
Summary
The need for the use of multiple drugs is common, as patients often present with numerous chronic diseases. To improve commodity and drug adherence, several medications are often administered concomitantly. This may represent a preferred clinical strategy, the administration of two or more drugs at overlapping times increases the likelihood of drug–drug interactions [1,2]. Substrates Substrates are drugs that bind to the active site of an enzyme and are transformed into metabolites whmileetabSbeuoiblnistgetrsaptwreeshsiealenretbeidnirnugtghpsisrtehasaectntitvbieinndstihtteios. A substrate can exhibit varying binding affinity for an active site depending on their chemical structure and physical properties. Based on their binding affinity for a specific enzyme, substrates can be classified into weak, intermediate, and strong affinity substrates. Advanced clinical decision support systems (such as MedWiseTM) depict the various degrees of affinity by different colors: light yellow (weak), dark yellow (intermediate), and orange (strong affinity)
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