title: High-performance liquid chromatography analysis, preliminary pharmacokinetics, metabolism and renal excretion of methylprednisolone with its C6 and C20 hydroxy metabolites in multiple sclerosis patients receiving high-dose pulse therapy.
abstract: A gradient eluent HPLC analysis in human plasma and urine was developed and validated for methylprednisolone (MP), its prodrug methylprednisolone-21-hemisuccinate (MPS) with the metabolites 6beta-hydroxy-6alpha-methylprednisolone (MPA), 20-hydroxymethylprednisolone (MPC), 6beta-hydroxy-20alpha-hydroxymethylprednisolone (MPB), 6beta-hydroxy-20beta-hydroxymethylprednisolone (MPE), 20-carboxymethylprednisolone (MPD), methylprednisolone-glucuronide (MPF) and 21-carboxymethylprednisolone (MPX). The column was Cp Spherisorb C8 5 microm, 250 mm x 4.6 mm I.D. (Chrompack, Bergen op Zoom, The Netherlands) with a guard column 75 mm x 2.1 mm, packed with pellicular reversed-phase. The eluent was a mixture of acetonitrile and 0.067 M KH2PO4 buffer, pH 4.5. At t=O, the eluent consisted of 2% acetonitrile and 98% buffer (v/v). Over the following 35 min the eluent changed linearly until it attained a composition of 50% acetonitrile and 50% buffer (v/v). At 37 min (t=37) the eluent was changed over 5 min to the initial composition, followed by equilibration over 3 min. The flow-rate was 1.5 ml/min and UV detection was achieved at 248 nm. Preliminary pharmacokinetic data were obtained from one patient who showed illustrative plasma concentration-time curves and renal excretion-time profiles after a short-lasting infusion (0.5 h) of 1 g of methylprednisolone hemisuccinate. The half-life of prodrug methylprednisolone-21-hemisuccinate (MPS) was 0.3 h, that of metabolite MPX (21-carboxy MP) was 0.4 h and that of the parent drug methylprednisolone (MP) was 1.4 h. The half-lives of the metabolites are almost similar (4 h). The main compounds in the urine are methylprednisolone hemisuccinate (prodrug, 15.0%), methylprednisolone (parent drug, 14.6%), metabolite MPD (20-carboxy, 11.7%), and metabolite MPB (13.2%). The renal clearance values of metabolites MPB, MPC and MPD are approximately 500 ml/min, that of MP is 100 ml/min.
authors.affiliation: Institute of Anaesthesiology, Academic Hospital Nijmegen Sint Radboud, Nijmegen, The Netherlands. t.vree@anes.azn.nl
authors.forename: T B
authors.initials: TB
authors.lastname: Vree
authors.forename: A J
authors.initials: AJ
authors.lastname: Lagerwerf
authors.forename: C P
authors.initials: CP
authors.lastname: Verwey-van Wissen
authors.forename: P J
authors.initials: PJ
authors.lastname: Jongen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008775:Methylprednisolone / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine
chemical_list: D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone