Editing Azithromycin (section)

=== Drugs metabolized by CYP3A4 ===
[[CYP3A4]] is an enzyme that metabolizes many drugs in the liver. Some drugs can inhibit CYP3A4, which means they reduce its activity and increase the blood levels of the drugs that depend on it for elimination. This can lead to adverse effects or drug-drug interactions.<ref name="pmid32807049">{{cite journal |vauthors=Zhang L, Xu X, Badawy S, Ihsan A, Liu Z, Xie C, Wang X, Tao Y |title=A Review: Effects of Macrolides on CYP450 Enzymes |journal=Curr Drug Metab |volume=21 |issue=12 |pages=928–937 |date=2020 |pmid=32807049 |doi=10.2174/1389200221666200817113920 |s2cid=221162650 |url=https://eurekaselect.com/article/download/184894 |access-date=2 February 2024 |archive-date=2 February 2024 |archive-url=https://web.archive.org/web/20240202144113/https://eurekaselect.com/article/download/184894 |url-status=live |url-access=subscription }}</ref>

Azithromycin is a member of macrolides that are a class of antibiotics with a cyclic structure with a [[lactone]] ring and sugar moieties. Macrolides can inhibit CYP3A4 by a mechanism called mechanism-based inhibition (MBI), which involves the formation of reactive metabolites that bind covalently and irreversibly to the enzyme, rendering it inactive. Mechanism-based inhibition is more serious and long-lasting than reversible inhibition, as it requires the synthesis of new enzyme molecules to restore the activity.<ref name="pmid31628882">{{cite journal |vauthors=Hougaard Christensen MM, Bruun Haastrup M, Øhlenschlaeger T, Esbech P, Arnspang Pedersen S, Bach Dunvald AC, Bjerregaard Stage T, Pilsgaard Henriksen D, Thestrup Pedersen AJ |title=Interaction potential between clarithromycin and individual statins-A systematic review |journal=Basic Clin Pharmacol Toxicol |volume=126 |issue=4 |pages=307–317 |date=April 2020 |pmid=31628882 |doi=10.1111/bcpt.13343 |url=https://findresearcher.sdu.dk/ws/files/158846448/Interaction_Potential_between_Clarithromycin_and_Individual_Statins_a_Systematic_Review.pdf |access-date=2 February 2024 |archive-date=2 February 2024 |archive-url=https://web.archive.org/web/20240202140200/https://findresearcher.sdu.dk/ws/files/158846448/Interaction_Potential_between_Clarithromycin_and_Individual_Statins_a_Systematic_Review.pdf |url-status=live }}</ref>

The degree of mechanism-based inhibition by macrolides depends on the size and structure of their lactone ring. Clarithromycin and erythromycin have a 14-membered lactone ring, which is more prone to demethylation by CYP3A4 and subsequent formation of nitrosoalkenes, the reactive metabolites that cause mechanism-based inhibition. Azithromycin, on the other hand, has a 15-membered lactone ring, which is less susceptible to demethylation and nitrosoalkene formation. Therefore, azithromycin is a weak inhibitor of CYP3A4, while clarithromycin and erythromycin are strong inhibitors which increase the area under the curve (AUC) value of co-administered drugs more than five-fold.<ref name="pmid31628882"/> AUC it is a measure of the drug exposure in the body over time. By inhibiting CYP3A4, macrolide antibitiotics, such as [[erythromycin]] and [[clarithromycin]], but not azithromycin, can significantly increase the AUC of the drugs that depend on it for clearance, which can lead to higher risk of adverse effects or drug-drug interactions. Azithromycin stands apart from other macrolide antibiotics because it is a weak inhibitor of CYP3A4, and does not significantly increase AUC value of co-administered drugs.<ref name="pmid11012550">{{cite journal |vauthors=Westphal JF |title=Macrolide - induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin |journal=Br J Clin Pharmacol |volume=50 |issue=4 |pages=285–95 |date=October 2000 |pmid=11012550 |pmc=2015000 |doi=10.1046/j.1365-2125.2000.00261.x }}</ref>

The difference in CYP3A4 inhibition by macrolides has clinical implications, for example for people who take [[statin]]s, which are [[cholesterol]]-lowering drugs that are mainly metabolized by CYP3A4. Co-administration of clarithromycin or erythromycin with statins can increase the risk of statin-induced [[myopathy]], a condition that causes muscle pain and damage. Azithromycin, however, does not significantly affect the pharmacokinetics of statins and is considered a safer alternative than other macrolide antibiotics.<ref name="pmid31628882"/>