<p>Diphenhydramine undergoes rapid and extensive first-pass metabolism <sup class="text-reference-group"><a class="reference-popover-link" data-content="Benylin Chesty Coughs UK MHRA Product Information" href="#reference-F3394">18</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Nytol One-A-Night (diphenhydramine hydrochloride) Monograph" href="#reference-L5287">13</a>,<a class="reference-popover-link" data-content="Rodrigues WC, Castro C, Catbagan P, Moore C, Wang G: Immunoassay screening of diphenhydramine (Benadryl(R)) in urine and blood using a newly developed assay. J Anal Toxicol. 2012 Mar;36(2):123-9. doi: 10.1093/jat/bkr015. (PubMed ID 22337782)" href="#reference-A174577">8</a></sup>. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite) <sup class="text-reference-group"><a class="reference-popover-link" data-content="Benylin Chesty Coughs UK MHRA Product Information" href="#reference-F3394">18</a>,<a class="reference-popover-link" data-content="Rodrigues WC, Castro C, Catbagan P, Moore C, Wang G: Immunoassay screening of diphenhydramine (Benadryl(R)) in urine and blood using a newly developed assay. J Anal Toxicol. 2012 Mar;36(2):123-9. doi: 10.1093/jat/bkr015. (PubMed ID 22337782)" href="#reference-A174577">8</a></sup>. Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite <sup class="text-reference-group"><a class="reference-popover-link" data-content="Rodrigues WC, Castro C, Catbagan P, Moore C, Wang G: Immunoassay screening of diphenhydramine (Benadryl(R)) in urine and blood using a newly developed assay. J Anal Toxicol. 2012 Mar;36(2):123-9. doi: 10.1093/jat/bkr015. (PubMed ID 22337782)" href="#reference-A174577">8</a></sup>. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well <sup class="text-reference-group"><a class="reference-popover-link" data-content="Benylin Chesty Coughs UK MHRA Product Information" href="#reference-F3394">18</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Nytol One-A-Night (diphenhydramine hydrochloride) Monograph" href="#reference-L5287">13</a>,<a class="reference-popover-link" data-content="Rodrigues WC, Castro C, Catbagan P, Moore C, Wang G: Immunoassay screening of diphenhydramine (Benadryl(R)) in urine and blood using a newly developed assay. J Anal Toxicol. 2012 Mar;36(2):123-9. doi: 10.1093/jat/bkr015. (PubMed ID 22337782)" href="#reference-A174577">8</a></sup>. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged <sup class="text-reference-group"><a class="reference-popover-link" data-content="Benylin Chesty Coughs UK MHRA Product Information" href="#reference-F3394">18</a>,<a class="reference-popover-link" data-content="Electronic Medicines Compendium: Nytol One-A-Night (diphenhydramine hydrochloride) Monograph" href="#reference-L5287">13</a>,<a class="reference-popover-link" data-content="Rodrigues WC, Castro C, Catbagan P, Moore C, Wang G: Immunoassay screening of diphenhydramine (Benadryl(R)) in urine and blood using a newly developed assay. J Anal Toxicol. 2012 Mar;36(2):123-9. doi: 10.1093/jat/bkr015. (PubMed ID 22337782)" href="#reference-A174577">8</a></sup>. The metabolites are further conjugated with glycine and glutamine and excreted in urine <sup class="text-reference-group"><a class="reference-popover-link" data-content="Electronic Medicines Compendium: Nytol One-A-Night (diphenhydramine hydrochloride) Monograph" href="#reference-L5287">13</a></sup>.</p><p>Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19 <sup class="text-reference-group"><a class="reference-popover-link" data-content="Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K: Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8. doi: 10.1124/dmd.106.012088. Epub 2006 Oct 4. (PubMed ID 17020955)" href="#reference-A174574">7</a></sup>. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified <sup class="text-reference-group"><a class="reference-popover-link" data-content="Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K: Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8. doi: 10.1124/dmd.106.012088. Epub 2006 Oct 4. (PubMed ID 17020955)" href="#reference-A174574">7</a></sup>. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine <sup class="text-reference-group"><a class="reference-popover-link" data-content="Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, Chiba K: Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8. doi: 10.1124/dmd.106.012088. Epub 2006 Oct 4. (PubMed ID 17020955)" href="#reference-A174574">7</a></sup>.</p><p class="d-none d-sm-block"><strong>Hover over products below to view reaction partners</strong></p>