The pharmacokinetics of methotrexate after intravenous administration of methotrexate‐loaded proliposomes to rats

Abstract

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX-loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg-1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (Cp), the area under the plasma concentration-time curve (AUC, 639 versus 913 micrograms min mL-1), the terminal half-life (t1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (Vss, 98.1 versus 2800 mL kg-1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min-1 kg-1), renal clearance (CLR, 4.49 versus 2.78 mL min-1 kg-1), non-renal clearance (CLNR, 7.50 versus 5.99 mL min-1 kg-1), and the amount of MTX excreted in urine (Xu, 808 versus 685 micrograms, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX-loaded liposomes (formed immediately after hydration of MTX-loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and Vss from treatment II), and MTX is slowly released from MTX-loaded liposomes (higher t1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher Cp and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t1/2, MRT, and Vss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX-loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX-loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX-loaded proliposomes when incubated with phosphate-buffered saline (PBS), rat plasma, or rat liver homogenate.

Stealth Nanogels of Histinylated Poly Ethyleneimine for Sustained Delivery of Methotrexate in Collagen-Induced Arthritis Model

“…The corresponding MRT and t 1/2 increased about six-fold after loading in the nanogels (Table II). Similarly, Park et al (46) and Kim et al (47) showed a comparable superior pharmacokinetics of different MTX liposomes after single i.v. injection of the equivalent doses.…”

Liposomes as Vehicles for Enhancing Drug Delivery Via Skin Routes

“…The resulting liposomes may act as a sustained-release dosage form of the loaded drugs. Proliposomes can be administered by various routes, including oral, intranasal, and intravenous administrations [107][108][109]. To extend the applications of proliposomes and proniosomes, the systemic delivery of drugs across the skin was developed.…”

Liposome mediated-CYP1A1 gene silencing nanomedicine prepared using lipid film-coated proliposomes as a potential treatment strategy of lung cancer

“…Proliposomes have also been investigated for nasal delivery of propranolol hydrochloride and nicotine (Ahn et al, 1995;Jung et al, 2000a), and for parenteral administration of antifungal drugs (e.g. amphotericin B) (Payne et al, 1987), and anticancer agents such as methotrexate (Park et al, 1994) and doxorubicin (Wang et al, 2000), and for transdermal delivery of nicotine (Hwang et al, 1997;Jung et al, 2000b). We have previously shown that proliposomes made by coating sucrose with lipid films can generate inhalable liposomes when hydrated in situ within medical nebulizers (Elhissi et al, 2012).…”