**Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice**

**Malavika Deodhar 1, Sweilem B Al Rihani 1, Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1, Jacques Turgeon 1,2 and Veronique Michaud 1,2,\***


 **\***Correspondence:vmichaud@trhc.com;Tel.:+1-856-938-8697

 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020

**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 a ffinity 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 managemen<sup>t</sup> 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 managemen<sup>t</sup> 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 di fferent types of mechanism-based inhibition, along with illustrative examples of how mechanism-based inhibition might a ffect prescribing and clinical behaviors.

**Keywords:** drug–drug interactions; mechanism-based inhibition; competitive inhibition; non-competitive inhibition; substrate; inhibitor; cytochromes P450
