References
1: Cancer Chemother Pharmacol 1996;37(5):409-14 Related Articles, Links
Clinical and experimental pharmacokinetic interaction between
6-mercaptopurine and methotrexate.
Innocenti F, Danesi R, Di Paolo A, Loru B, Favre C, Nardi M, Bocci G,
Nardini D, Macchia P, Del Tacca M.
Institute of Medical Pharmacology, University of Pisa, Italy.
Clinical and experimental pharmacokinetic interaction between
6-mercaptopurine (6-MP) and methotrexate (MTX) was investigated in
patients as well as in rats and in HL-60 human leukemic cells. Ten
children affected by acute lymphoblastic leukemia (ALL) in remission
received daily doses of 6-MP given at 25 mg/m2 and i.v. infusion of
high-dose MTX at 2 or 5 g/m2 once every other week. When 6-MP was given
alone, the mean peak plasma concentration (Cmax) and area under the
curve (AUC) of 6-MP were 72.5 ng/ml and 225.3 h ng ml(-1). Concurrent
treatment with MTX at 2 or 5 g/m2 resulted in a mean increase of 108%
and 121% in the Cmax and of 69% and 93% in the AUC, respectively. In
rats treated with an oral dose of 6-MP at 75 mg/m2, MTX given i.p. at 5
g/m2 produced mean increases of 110% and 230% in the Cmax and AUC of
6-MP, respectively. In HL-60 human leukemic cells incubated with 6-MP at
250 ng/ml, the cumulative intracellular concentration of 6-thioguanine
and 6-MP nucleotides was not significantly modified by treatment with 20
micrograms/ml of MTX. The present findings indicate that high-dose MTX
enhances the bioavailability of 6-MP as evidenced by the observed
increases in the plasma Cmax and AUC of 6-MP in humans and animals.
PMID: 8599862 [PubMed - indexed for MEDLINE]
------
1: Clin Pharmacol Ther 1987 Apr;41(4):384-7 Related Articles, Links
The effect of methotrexate on the bioavailability of oral
6-mercaptopurine.
Balis FM, Holcenberg JS, Zimm S, Tubergen D, Collins JM, Murphy RF,
Gilchrist GS, Hammond D, Poplack DG.
Fourteen children (aged 3 to 14 years) with average-risk acute
lymphoblastic leukemia were studied after an oral dose of
6-mercaptopurine (6-MP) (75 mg/m2) administered alone and, on the next
day, concurrently with oral methotrexate (20 mg/m2). When 6-MP was
administered alone, both the peak plasma concentration (15 to 150 ng X
ml-1) and the AUC (36 to 340 ng X ml-1 X hr) were highly variable.
Concurrent methotrexate resulted in a 31% increase in the AUC (P less
than 0.01) and a 26% increase in peak plasma levels (P less than 0.05)
of 6-MP. The AUC of methotrexate correlated with the degree of increase
in 6-MP plasma concentrations. These findings are consistent with
previous in vitro studies demonstrating that methotrexate is an
inhibitor of xanthine oxidase, the enzyme that catabolizes 6-MP to the
inactive metabolite thiouric acid. Although the increases in 6-MP AUC
and peak plasma concentrations resulting from concurrent methotrexate
administration were statistically significant, this interaction is
probably not clinically significant at standard low oral doses of
methotrexate in light of the wide interpatient variability in these
pharmacokinetic parameters of 6-MP.
PMID: 3470165 [PubMed - indexed for MEDLINE]
------
1: J Pediatr Hematol Oncol 1997 Mar-Apr;19(2):102-9 Related Articles,
Books, LinkOut
Impact of morning versus evening schedule for oral methotrexate and
6-mercaptopurine on relapse risk for children with acute lymphoblastic
leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO).
Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O.
Section of Clinical Hematology and Oncology, Juliane Marie Center,
University Hospital, Copenhagen, Denmark.
PURPOSE: To study the risk of non-B-cell acute lymphoblastic leukemia
(ALL) relapse in relation to the routines of administration of oral
methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E)
levels of the intracellular cytotoxic metabolites, that is, MTX
polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN).
PATIENTS AND METHODS: E-MTX and E-6TGN levels were measured at least
three times (medians, eight and nine) in 294 children with non-B-cell
ALL during oral MTX and 6MP therapy. For each patient, we registered (a)
the individual circadian schedule of drug administration and (b) the
coadministration of food, and (c) calculated a mean (m) of all E-MTX and
E-6TGN measurements and (d) the product of mE-MTX and mE-6TGN
(mE-MTX*6TGN), due to their synergistic action. RESULTS: A total of 42
patients were on a morning schedule, 219 were on an evening schedule,
and 33 had miscellaneous routines. A total of 149 patients took the
drugs with meals, 106 took the drugs between meals, and 39 had varying
routines. With a median follow-up of 78 months, ALL has recurred in 66
patients. The patients on an evening schedule had a superior outcome
[probability of event-free survival (pEFS) = 0.82 +/- 0.03 vs. 0.57 +/-
0.08; p = 0.0002], whereas the coadministration of food did not
significantly influence outcome. Patients with a mE-MTX*6TGN < 813
[product of median mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol
Hb)] had an inferior outcome (pEFS = 0.70 +/- 0.04 vs. 0.85 +/- 0.03; p
= 0.003), even if only patients on an evening schedule were analyzed.
Thus, 109 patients on the MTX/6MP evening schedule with an mE-MTX*6TGN <
or = 813 (nmol/mmol Hb)2 had a pEFS of 0.89 +/- 0.03 and a probability
of continuous hematopoietic remission of 0.91 +/- 0.03. CONCLUSIONS: An
evening schedule should be recommended for oral MTX/6MP maintenance
therapy. The value of individual dose adjustments by E-MTX and E-6TGN
remains to be determined in prospective randomized trials.
PMID: 9149738 [PubMed - indexed for MEDLINE]
------
1: Gen Pharmacol 1999 Oct;33(4):341-6 Related Articles, Links
The interaction of 6-mercaptopurine (6-MP) and methotrexate (MTX).
Giverhaug T, Loennechen T, Aarbakke J.
Department of Pharmacology, Institute of Pharmacy, University of
Tromso, Norway. trudeg@farmasi.uit.no
The antimetabolites 6-mercaptopurine (6-MP) and methotrexate (MTX)
are the cornerstones in the maintenance treatment of children's
acute lymphoblastic leukemia (ALL). The biochemical mechanisms
underlying the increased therapeutic efficacy of the combination of
these drugs have not yet been elucidated. However, both drugs
interact with important pathways. such as purine de novo synthesis
(PDNS), purine salvage, and methylation reactions. A review of the
mechanistic aspects of the interactions between 6-MP and MTX is
given.
Publication Types:
Review
Review, Tutorial
PMID: 10523073 [PubMed - indexed for MEDLINE]