title: Enhancement of tissue delivery and receptor occupancy of methylprednisolone in rats by a liposomal formulation.
abstract: A liposomal formulation of methylprednisolone (L-MPL) was developed to improve localization of this immunosuppressant in lymphatic tissues. Liposomes containing MPL were formulated from a mixture of phosphatydylcholine and phosphatydylglycerol (molar ratio, 9:1) and sized by extrusion through a 0.1-micron membrane. Male Sprague-Dawley rats received a bolus dose of 2 mg/kg of L-MPL or free MPL in solution (control). Samples of blood, spleen, liver, thymus, and bone marrow were collected at intervals over a 66-hr period. Concentrations of MPL in plasma and organs and free cytosolic glucocorticoid receptors (GCR) in spleen and liver were determined. The plasma MPL profiles for free and L-MPL were bi- and triexponential. Although the alpha phase kinetics of both dosage forms were similar, L-MPL showed a substantially slower elimination phase than did free drug. Incorporation of MPL into liposomes caused the following increases: terminal half-life, from 0.48 (MPL) to 30.13 hr (L-MPL); MRT, from 0.42 to 11.95 hr, Vss, from 2.10 to 21.87 L/kg; and AUC, from 339 to 1093 ng x hr/mL. Uptake of liposomes enhanced significantly the delivery of drug to lymphatic tissues and liver; AUC tissue:plasma ratios for spleen increased 77-fold; for liver, 9-fold; and for thymus, 27-fold. The duration of GCR occupancy was extended 10-fold in spleen and 13-fold in liver by the liposomal formulation. Lymphatic tissue selectivity and extended receptor binding of liposome-delivered MPL offer promise for enhanced immunosuppression.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo 14260.
authors.forename: E V
authors.initials: EV
authors.lastname: Mishina
authors.forename: R M
authors.initials: RM
authors.lastname: Straubinger
authors.forename: N A
authors.initials: NA
authors.lastname: Pyszczynski
authors.forename: W J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004337:Drug Carriers; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010713:Phosphatidylcholines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D011965:Receptors, Glucocorticoid; D008775:Methylprednisolone