The Impact of Liposomal Formulations on the Release and Brain Delivery of Methotrexate: An In Vivo Microdialysis Study.
The impact of liposomal formulations on the in vivo release and brain delivery of methotrexate (MTX) was quantitatively assessed in rats. Two PEGylated liposomal MTX formulations based on hydrogenated soy phosphatidylcholine (HSPC) or egg-yolk phosphatidylcholine (EYPC) were prepared. The drug release and uptake into the brain after intravenous administration of both formulations were compared with unformulated MTX by determining the released, unbound MTX in brain and plasma using microdialysis. Total MTX concentrations in plasma were determined using regular blood sampling. The administration of both high- and low-dose EYPC liposomes resulted in 10 times higher extent of MTX release in plasma compared to that obtained from HSPC liposomes (p < 0.05). MTX itself possessed limited brain uptake with steady-state unbound brain-to-plasma concentration ratio (Kp,uu) of 0.10 ± 0.06. Encapsulation in HSPC liposomes did not affect MTX brain uptake (Kp,uu0.11 ± 0.05). In contrast, EYPC liposomes significantly improved MTX brain delivery with a 3-fold increase of Kp,uu(0.28 ± 0.14 and 0.32 ± 0.13 for high- and low-dose EYPC liposomal MTX, respectively, p < 0.05). These results provide unique quantitative evidence that liposomal formulations based on different phospholipids can result in very different brain delivery of MTX.
Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Box 591, Uppsala 75124, Sweden.
Yang
Y
Hu
Eyesiu Medicines BV, J.H. Oortweg 19, Leiden 2333, The Netherlands.
Jaap
J
Rip
Eyesiu Medicines BV, J.H. Oortweg 19, Leiden 2333, The Netherlands; 2-BBB Medicines BV, J.H. Oortweg 19, Leiden 2333, The Netherlands.
Pieter J
PJ
Gaillard
Division of Pharmacology, Cluster Systems Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
Elizabeth C M
ECM
de Lange
Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab, Uppsala University, Box 591, Uppsala 75124, Sweden. Electronic address: mhu@farmbio.uu.se.
Margareta
M
Hammarlund-Udenaes
D000818:Animals; D001921:Brain / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017551:Microdialysis / Q000379:methods*; D010316:Particle Size; D010713:Phosphatidylcholines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D053719:Tandem Mass Spectrometry / Q000379:methods
D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D011092:Polyethylene Glycols; D008727:Methotrexate
blood-brain barrier; brain delivery; in vivo release; liposome; methotrexate; microdialysis; nanocarrier