Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate-bearing negatively charged liposomes to rats

Yi N. Jeong, Sun H. Lee, Myung G. Lee, Sung J. Hwang, Chong 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), freshly prepared MTX-bearing negatively charged liposomes (large unilamellar vesicles), NLUV (treatment II), and empty NLUV mixed manually with free MTX (treatment III), 4 mg kg-1 as free MTX to rats using an HPLC assay. After i.v. infusion over 1 min, the plasma concentrations of MTX (CP), area under the plasma concentration-time curve (AUC, 173 vs 402 μg ml min-1), terminal half-life (t 1 2, 24.0 vs not determined), mean residence time (MRT, 13.0 vs 83.5 min) and volume of distribution at steady state (Vss, 289 vs 942 ml kg-1) increased significantly, however, total body clearance (CL, 23.1 vs 9.94 ml min-1 kg-1), renal clearance (CLR, 8.38 vs 3.39 ml min-1 kg-1), nonrenal clearance (clNR, 14.6 vs 6.53 ml min-1 kg-1) and the amount of MTX excreted in urine (Xu, 415 vs 333 μg) 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 NLUV are entrapped in the tissues, the rest being present in plasma (increase in MRT and Vss from treatment II), and slow release of MTX from MTX-bearing NLUV (increase in t 1 2from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of the free MTX and MTX in MTX-bearing NLUV (increase in CP and AUC, and decrease in CL from treatment II). Saturable formation of 7-OH-MTX from MTX was observed in rabbit blood, nonlinear disposition of MTX also being found in rabbits (decrease in Xu and CLR from treatment II). After i.v. infusion over l min, some pharmacokinetic parameters of MTX, such as t 1 2 (24.0 vs 56.9 min), AUC (173 vs 234 (μg min ml-1), MRT (13.0 vs 29.8 min), CL (23.1 vs 17.1 ml min-1 kg-1), CLR (8.38 vs 5.66 ml min-1 kg-1), clNR (14.6 vs 11.4 ml min-1 kg-1) and Xu (415 vs 290 μg) were significantly different between treatments I and III, however, the differences appeared to be smaller than those between treatments I and II. After both i.v. and i.m. administration, the amount of MTX remaining per g tissue, or the tissue-to-plasma ratio (T/P) of MTX at 30 min after injection was significantly reduced in the kidney, small intestine, large intestine and stomach from treatment II when compared with that from treatment I. This implies that the side effects of MTX on the kidney and GI tract could be reduced after i.v. or i.m. administration of MTX-bearing NLUV when compared with those of free MTX. The encapsulation efficiency of MTX in MTX-bearing NLUV was 4.16% and the MTX was released slowly from MTX-bearing NLUV when incubated in phosphatebuffered saline, rat plasma and rat liver homogenate.

Original languageEnglish
Pages (from-to)35-46
Number of pages12
JournalInternational Journal of Pharmaceutics
Issue number1-3
Publication statusPublished - 1994 Feb 7

Bibliographical note

Funding Information:
This work was supportedi n part by a research grant (KOSEF 90-03-00-06f)r om the Korea Science & EngineeringF oundation in 1990-1993.

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science


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