Methotrexate

Toxicology of Methotrexate

Christopher Dae Lee

BIO 4344.01

04/21/2015

Introduction

Methotrexate (MTX) was originally developed as amethopterin, a chemotherapeutic drug. It is one of the most widely used anticancer drugs and has been widely studied due to its mechanism of action. Some of these cancers include: breast, leukemia, lymphoma, lung, bladder, testicular, osteosarcomas, and various other cancers. In 1985, MTX was show to be a potent and efficient treatment option for those with Rheumatoid arthritis [1]. In addition, it is used in the treatment of autoimmune diseases, ectopic pregnancies, medical abortions, and the prevention of graft-versus-host disease after transplantation [2] .

MTX is on the World Health Organization’s list of essential medicines. The list of essential WHO essential medicine list are selected due to disease prevalence, evidence of efficacy and safety, in addition to cost effectiveness. MTX is also known as Amethopterin, Methotrexate Sodium and trade names of Rheumatrex® and Trexall™. Its specificity of action as a tight-binding enzyme inhibitor makes it a much studied compound [3].

Physical and Chemical Properties of Methotrexate

MTX has a molecular formula of C20H22N8O5 with a 2D structure, as shown in Figure 1. The molecular formula is 454.46 g/mol. It is an orange-brown, crystalline powder with a melting point of 195oC. The solubility of MTX varies as would be expected. In water, alcohol and chloroform MTX is insoluble while in dilute alkaline solutions it is soluble, and slightly soluble in dilute hydrochloric acid (4). As shown in figure 1, it has two carboxylic acid groups with pKa values of 2.15 and 3.8 [5]. The yellow crystals form from decomposition at its melting point of 185-204oC in dilute hydrogen chloride [6].

MTX is only slightly different from the essential vitamin, folic acid (figure 2) by the amino group where a hydroxyl group is on the pteridine ring. Folic Acid (Vitamin B9) aids in the production...