5-Monobutyl methotrexate

Macaca mulatta (adult, 10-15 kg, male and female)^[1]

27 mg (bolus); 10 g/m² (1.25-hour infusion); 10 g/m² (4-hour infusion)

i.v. (bolus over 1-2 minutes); i.v. (infusion over 1.25 hours); i.v. (infusion over 4 hours)

Accounted for 67%-94% of total serum radioactivity for up to 60 min, with [³H]MTX comprising 4%-13% and only traces of other products after intravenous bolus.
Reached approximately equal proportions with MTX in serum at 2 h after intravenous bolus.
Was the major species in urine over 60 minutes and up to 4 hours, declining from 95% to 54% of total urinary radioactivity, while MTX increased to 31% and other products increased to 15% after intravenous bolus.
Reached free serum level of 1×10^-4 M at end of 1.25-h infusion, declining to 7×10^-6 M over 5 h.
Peaked at 1.5×10^-5 M in CSF after 1.25-h infusion, with CSF/serum ratios increasing from 0.15 at 2 h post-infusion to 1.0 at 5 h post-infusion.
Showed free serum MTX ranging from 1×10^-5 M to 4.8×10^-6 M over 5 h, with CSF MTX ranging from 4.7×10^-6 M to 7.5×10^-6 M, and CSF/serum MTX ratios consistently above 0.5 after 1.25-hour infusion.
Remained detectable in serum at 24 hours, with MTX present in CSF at 24 hours (≈4×10^-6 M) after 1.25-hour infusion.
Had free serum levels roughly 50% lower than after 1.25-hour infusion at corresponding time points after 4-hour infusion.
Showed CSF levels following a similar lower pattern to serum after 4-hour infusion, with CSF/serum ratios increasing from 0.18 at end of infusion to 1.2 at 3 hours post-infusion.
Was below 1×10^-6 M in free serum at 24 hours, while remaining above 4×10^-6 M in CSF after 4-hour infusion.
Showed free serum MTX peaking at 5.4×10^-4 M at 2 hours post-infusion, with MTX undetectable in CSF (<1×10^-6 M) at all time points after 4-hour infusion.