Pharmacokinetics of methotrexate and its 7‐OH metabolite in cancer patients treated with different high‐methotrexate dosage regimens

The pharmacokinetics of methotrexate (MX) and 7‐OH methotrexate (MXOH) was studied in 18 cancer patients treated with 6‐hr intravenous (i.v.) infusion of 100 mg/kg (S), 80 mg/kg preceded by 30 mg/kg i.v. loading dose (C). Simultaneous analysis of MX and MXOH was performed by high‐performance liquid chromatography. The data for MX conformed to a 2‐compartment model with overall mean ± SD for beta k12, k21, and k13 of 0.225 ± 0.196, 1.33 ± 1.44, 0.954 ± 1.06, and 0.994 ± 1.28 hr −1 , repectively. The total body clearance, Vc, and V‐beta were 0.123 ± 0.037 1/hr.kg, 0.15 ± 0.122 l/kg, and 0.965 ± 0.87 l/kg, respectively. No significant differences ( p > 0.05) in these parameters, attributable to the difference in regimens, were observed. With regimens A, B and C, the maximum observed concentrations of MXOH occurred at 9.2, 11.5, and 9.2 hr and the mean ± SD values of these concentrations were 15.02 ± 14.91 ± 9.95 μm, respectively. With regimens A and C, maximum obserced concentration of MX equal to 231 ± 67.1 and 204 ± 69.5 μm, occurred at 0.5 and 6 hr, respectively. Only with regimen B was a steady‐state MX concnetration of 179 μm, achieved throughout infusion; this regimen is therefore highly advantageours for high‐dose MX treatment.