<p>Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. (PubMed ID 24284432)" href="#reference-A180322">1</a>,<a class="reference-popover-link" data-content="FDA Approved Drug Products: Methotrexate Injection" href="#reference-L7180">7</a></sup> Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. (PubMed ID 24284432)" href="#reference-A180322">1</a>,<a class="reference-popover-link" data-content="FDA Approved Drug Products: Methotrexate Injection" href="#reference-L7180">7</a></sup> A small amount of methotrexate is also converted to 7-hydroxymethotrexate.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Inoue K, Yuasa H: Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9. Epub 2013 Nov 26. (PubMed ID 24284432)" href="#reference-A180322">1</a>,<a class="reference-popover-link" data-content="FDA Approved Drug Products: Methotrexate Injection" href="#reference-L7180">7</a></sup></p><p class="d-none d-sm-block"><strong>Hover over products below to view reaction partners</strong></p>