|
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 liposmes (large unilamellar vesicles), OLUVs (treatment Ⅱ) and free MTX mixed manually with empty OLUVs (treatment Ⅲ), 4㎎/㎏ as free MTX to rats. After i.v. infusion in 1 min, the plasma concentrations of MTX (C_p), area under the plasma concentration-time curve (AUC, 173 vs. 1110 ㎍ ㎖/min), terminal half-life (t_1/2, 24 ·0 min vs. not determined), mean residence time (MRT, 13 ·0 vs. 165 min) and apparent volume of distribution at steady state (V_ss, 289 vs. 584 ㎖/㎏) increased significantly; however, total body clearance (Cl, 23 ·1 vs. 3 ·61 ㎖/min/㎏), renal clearance (Cl_R, 8 ·38 vs. 1 ·88 ㎖/min/㎏) and nonrenal clearance (Cl_NR' 14·6 vs. 1·66 ㎖/min㎏) 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 V_ss from treatment Ⅱ). MTX was slowly released from the MTX-bearing OLUVs (increase in t_1/2 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 C_p and AUC, and decrease in Cl from treatment Ⅱ). Some pharmacokinetic parameters of MTX, such as t_1/2 (24 ·0 vs. 58 ·2 min), MRT(13 ·0 vs. 23 ·3 min) and V_ss (289 vs. 456 ㎖/㎏) 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, t_1/2 (37 ·2 min vs. not determined) and the total amounts of MTX excreted in urine (X_u, 319 vs. 171 ㎍) 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.
|