Methotrexate increases red blood cell concentrations of 6-methylmercaptopurine ribonucleotide in rats in vivo

Abstract

Single bolus doses of MTX increase the concentration of MMPRP in rats given daily s.c. doses of 6-MP, with no effect on 6-TGN concentration or TPMT activity.

Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia

“…This is the first study to assess the impact of methotrexate on the leukemic blast disposition, plasma pharmacokinetics, and pharmacodynamics of mercaptopurine in patients with newly diagnosed ALL. Methotrexate has been proposed to synergize with mercaptopurine by inhibiting de novo purine synthesis and thereby enhancing mercaptopurine's conversion to active thioguanine metabolites 5 , 6 , 7 , 8 . The methotrexate dosages effective in vitro are much lower than many of those shown to be effective clinically, 10 , 11 , 12 and a pharmacologic interaction has never been demonstrated in vivo in the target tissue.…”

“…Methotrexate has been proposed to synergize with mercaptopurine by inhibiting de novo purine synthesis and thereby enhancing mercaptopurine's conversion to active thioguanine metabolites. [5][6][7][8] The methotrexate dosages effective in vitro are much lower than many of those shown to be effective clinically, [10][11][12] and a pharmacologic interaction has never been demonstrated in vivo in the target tissue. The methotrexate and mercaptopurine dosages we studied were ones that have been incorporated into several recent clinical trials, [10][11][12]14,[16][17][18][19] and thus the in vivo pharmacologic data described herein provide a valuable complement to emerging clinical data in ALL.…”

“…In vitro studies have reported a synergistic effect of methotrexate on mercaptopurine or thioguanine 5 , 6 , 7 , 8 . Methotrexate's inhibition of de novo purine synthesis can lead to an increased concentration in phosphoribosylpyrophosphate, 5 , 9 a cofactor for the hypoxanthine phosphoribosyltransferase‐catalyzed conversion of mercaptopurine into thiopurine nucleotide monophosphate.…”

“…4 In vitro studies have reported a synergistic effect of methotrexate on mercaptopurine or thioguanine. [5][6][7][8] Methotrexate's inhibition of de novo purine synthesis can lead to an increased concentration in phosphoribosylpyrophosphate, 5,9 a cofactor for the hypoxanthine phosphoribosyltransferase-catalyzed conversion of mercaptopurine into thiopurine nucleotide monophosphate. Clinical studies have suggested that the combination of high-dose methotrexate with intravenous mercaptopurine is superior to low-dose methotrexate with mercaptopurine, [10][11][12] but direct evidence that high-dose methotrexate produces greater enhancement of thiopurine intracellular accumulation compared with that for low-dose methotrexate is lacking.…”

Advances in individual prediction of methotrexate toxicity: a review

“…An important exception is the combination with oral 6MP in both low‐ and high‐dose MTX therapy. This combination is biochemically and clinically supported, as MTX may increase the bioavailability of 6MP through inhibition of xanthine oxidase, which catabolises 6MP (Balis et al , 1987; Innocenti et al , 1996), and because MTX‐mediated inhibition of de novo purine synthesis increases intracellular levels of phosphoribosyl pyrophosphate, and thereby may increase both the formation of 6‐thioguanine nucleotides (the primary mediator of 6MP cytotoxicity) and their incorporation into DNA (Bokkerink et al , 1986; Giverhaug et al , 1997). When HD‐MTX (5·0 g/m 2 /24 h with Leucovorin rescue) is given together with oral 6MP (75 mg/m 2 ), approximately 40% of the patients will experience treatment interruption of a median of 10 d due to severe myelotoxicity (Schmiegelow & Bretton‐Meyer, 2001).…”