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The response to high-dose MTX (HD-MTX) where toxicity reflects variability in both drug exposure (determined renal clearance [ 13] and hepatic metabolism [ 14] i.e. by variants in kidney and liver transporters and enzymes) and in drug sensitivity of target tissues (i.e. by apoptosis, DNA repair and MTX target gene variants [ 3, 9]) is an examples of such multi-locus dependency.

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