Lj. Egan et al., Systemic and intestinal pharmacokinetics of methotrexate in patients with inflammatory bowel disease, CLIN PHARM, 65(1), 1999, pp. 29-39
Background: The pharmacokinetics of low-dose subcutaneous methotrexate have
not been determined throughout the standard weekly dosing interval, It is
not known whether methotrexate concentrations in the gastrointestinal tract
are sufficient for pharmacologic activity in inflammatory bowel disease.
Methods: Ten patients with inflammatory bowel disease participated in the s
tudy, After the patients started taking 15 or 25 mg subcutaneous methotrexa
te once a week, erythrocyte methotrexate concentration was measured every 2
weeks, The absorption; rectal distribution, metabolism, and elimination of
methotrexate were measured. The effect of methotrexate on proliferation of
an intestinal epithelial cell line was determined.
Results: After weekly subcutaneous administration of methotrexate was begun
, trough erythrocyte concentration rose to reach a plateau after 6 to 8 wee
ks, ranging from 150 to 300 nmol/L, More than 90% of subcutaneously adminis
tered methotrexate was rapidly excreted in the urine. The methotrexate plas
ma time course after subcutaneous administration fit a 2-compartment first-
order model with biphasic elimination and trough concentration of about 1 n
mol/L, Trough and peak methotrexate concentrations (mean value +/- SD) were
64 +/- 33 and 206 +/- 64 fmol/mg in the rectal mucosa and 4 +/- 3 and 51 /- 26 nmol/L in the rectal lumen, These methotrexate concentrations were in
the range found to be pharmacologically active against Caco-2 cell growth,
that is, a 50% inhibitory concentration from 10 to 46 nmol/L.
Conclusion: Subcutaneous methotrexate was well absorbed and distributed to
the site of the lesions in patients with inflammatory bowel disease. Methot
rexate was concentrated intracellularly in blood and in the rectum, The met
hotrexate concentration in the rectal mucosa remained within a pharmacologi
cally active range throughout the dosing interval. The findings represent a
pharmacologic explanation for the sustained efficacy of weekly methotrexat
e therapy.