Pharmacokinetics of methotrexate (MTX) and 7-hydroxymethotrexate (7-OH-MTX) in rats and evidence for the metabolism of MTX to 7-OH-MTX.
In pentobarbital anesthetized rats that received 4 mg/kg i.v. methotrexate (MTX) or 7-hydroxymethotrexate (7-OH-MTX), the pharmacokinetics of the two drugs were similar. Plasma concentrations of both drugs declined biexponentially, with terminal half-lives of 90.6 min for MTX and 97.2 min for 7-OH-MTX. The total clearance values were 9.2 and 9.6 ml x kg-1 x min-1, respectively. With MTX, 48.2% of the dose was excreted in the urine within 200 min and another 31.6% was recovered from the bile; 5.8% was metabolized to 7-OH-MTX and appeared in the bile. Plasma concentrations of the metabolite 7-OH-MTX after MTX administration were below the detection limit. Injected 7-OH-MTX was predominantly excreted into the bile (72.8% of the dose); only 11.2% could be recovered from the urine. Differences between the physicochemical properties of MTX and 7-OH-MTX or different affinities for active transport systems may account for the unequal importance of these two excretion pathways for the two compounds.
Fahrig
L
L
Department of Pharmacology, Medical University of Lübeck, Federal Republic of Germany.
Brasch
H
H
Iven
H
H
D000818:Animals; D001646:Bile / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
C011864:7-hydroxymethotrexate; D008727:Methotrexate