<p>Methotrexate clearance varies widely between patients and decreases with increasing doses.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Muhrez K, Benz-de Bretagne I, Nadal-Desbarats L, Blasco H, Gyan E, Choquet S, Montigny F, Emond P, Barin-Le Guellec C: Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance. Pharmacol Res. 2017 Apr;118:121-132. doi: 10.1016/j.phrs.2016.05.021. Epub 2016 May 19. (PubMed ID 27210722)" href="#reference-A180400">3</a></sup> Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken.<sup class="text-reference-group"><a class="reference-popover-link" data-content="Muhrez K, Benz-de Bretagne I, Nadal-Desbarats L, Blasco H, Gyan E, Choquet S, Montigny F, Emond P, Barin-Le Guellec C: Endogenous metabolites that are substrates of organic anion transporter's (OATs) predict methotrexate clearance. Pharmacol Res. 2017 Apr;118:121-132. doi: 10.1016/j.phrs.2016.05.021. Epub 2016 May 19. (PubMed ID 27210722)" href="#reference-A180400">3</a></sup></p>