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. 2018 Mar;11(2):106-108.
doi: 10.1111/cts.12513. Epub 2017 Nov 28.

Reverse Translation in Advancing Pharmacotherapy in Pediatric Rheumatology: A Logical Approach in Rare Diseases with Limited Resources

Mara L Becker  1   2 , Ryan S Funk  1   3
Affiliations

Reverse Translation in Advancing Pharmacotherapy in Pediatric Rheumatology: A Logical Approach in Rare Diseases with Limited Resources

Mara L Becker et al. Clin Transl Sci. 2018 Mar.
No abstract available

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Figures

Figure 1
Figure 1
Schematic of factors impacting response to pharmacotherapy. Major factors contributing to the observed variation in drug response among patients includes: heterogeneity in disease, variation in the disposition of the therapeutic agent (i.e., pharmacokinetic variation), and variation in the biochemical and physiological response to the drug (i.e., pharmacodynamic variation).
Figure 2
Figure 2
Schematic of intracellular pharmacokinetics and pharmacodynamics of methotrexate (MTX). Following transporter‐mediated uptake, MTX is reversibly metabolized to form a series of polyglutamated metabolites (MTX‐Glun). MTX inhibits the enzymatic conversion of folic acid (FA) to dihydrofolate (DHF), and DHF to tetrahydrofolate (THF), resulting in the depletion of cellular methylene‐THF (CH2THF), methenyl‐THF (CH=THF), and 5‐methyl‐THF (5mTHF). Depletion of the reduced cellular folate pool by MTX and inhibition of folate‐dependent enzymes by MTX‐Glun results in inhibition of purine, pyrimidine, and methionine biosynthesis.
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