Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate‐bearing neutral liposomes to rats

E. J. Bae, S. H. Lee, M. G. Lee, S. J. Hwang, Chong‐K ‐K Kim

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The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) and intramuscular (i.m.) injection of free MTX (treatment I), MTX‐bearing neutral liposomes (large unilamellar vesicles), OLUVs (treatment II) and free MTX mixed manually with empty OLUVs (treatment HI), 4 mg/kg as free MTX to rats. After i.v. infusion in 1 min, the plasma concentrations of MTX (Cp), area under the plasma concentration‐time curve (AUC, 173 vs. 1110 μg ml/min), terminal half‐life (t1/2, 24.0 min vs. not determined), mean residence time (MRT, 13.0 vs. 165 min) and apparent volume of distribution at steady state (Vss 289 vs. 584 ml/kg) increased significantly; however, total body clearance (CI, 23.1 vs. 3.61 ml/min/kg), renal clearance (ClR, 8.38 vs. 1.88 ml/min/kg) and nonrenal clearance (ClNR, 14.6 vs. 1.66 ml/min/kg) decreased significantly from treatment II when compared with the values from treatment I. This could be due to the fact that some of the MTX‐bearing OLUVs were entrapped in tissues and the others were present in plasma (increase in MRT and Vss from treatment II). MTX was slowly released from the MTX‐bearing OLUVs (increase in t1/2 from treatment II). With the present HPLC assay, the concentrations of MTX represent the sum of the free MTX and MTX in MTX‐bearing OLUVs (increase in Cp and AUC, and decrease in CI from treatment II). Some pharmacokinetic parameters of MTX, such as t1/2 (24.0 vs. 58.2 min), MRT (13.0 vs. 23.3 min) and Vss (289 vs. 456 ml/kg) were significantly different after i.v. administration of empty OLUVs (between treatments I and III); however, the differences seemed to be smaller than those between treatments I and II. After i.m. administration, t1/2 (37.2 min vs. not determined) and the total amounts of MTX excreted in urine (Xu, 319 vs. 171 μg) were significantly different after treatments I and II. After both i.v. and i.m. administration, the amount of MTX remaining per gram of tissue, and/or tissue to plasma ratio (T/P) of MTX were significantly reduced in the kidney, small intestine, large intestine or stomach from treatment II when compared with those from treatment I. This implies that the side‐effects of MTX on the kidney and gastrointestinal tract could be reduced after i.v. or i.m. administration of MTX‐bearing OLUVs rather than free MTX. The mean encapsulation efficiency of MTX in MTX‐bearing OLUVs was 3.88% and the MTX was released slowly from MTX‐bearing OLUVs when incubated in phosphate‐buffered saline, rat plasma and rat liver homogenate.

Original languageEnglish
Pages (from-to)393-404
Number of pages12
JournalJournal of Clinical Pharmacy and Therapeutics
Issue number6
Publication statusPublished - 1993 Dec

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)


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