title: Development and validation of LC-MS/MS assay for the determination of the prodrug Midodrine and its active metabolite Desglymidodrine in plasma of ascitic patients: Application to individualized therapy and comparative pharmacokinetics.
abstract: Midodrine (MD) is a prodrug that is converted after oral administration to Desglymidodrine (DMD). In this study, an LC-MS/MS assay was developed and validated for investigation of the pharmacokinetics of MD and DMD in non azotemic patients with liver cirrhosis and tense ascites. Results were compared to those noted with healthy volunteers following the adminstration of a single oral dose of MD. Sample preparation was performed by liquid-liquid extraction using t-butyl methyl ether. HPLC separation was carried out using RP C18 column (4.6mm×50mm, 5μm). Isocratic elution was performed using methanol:0.2% formic acid (70:30, v/v) as the mobile phase, at a flow rate of 0.7mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of MD and DMD. Analysis was carried out within 1.0min over a concentration range of 0.50-40.00ng/mL for the prodrug and its active metabolite. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the determination of the pharmacokinetic parameters of MD and DMD and personalized therapy was demonstrated in healthy volunteers and ascitic patients. Results revealed significant differences in pharmacokinetic parameters among the studied groups. Such differences were explained on the basis of the medical condition and co-adminstered medications exerting possible drug-drug interaction. Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Egyptian Russian University, Egypt.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Ali
authors.affiliation: Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Egypt; Bioanalysis Research Group, Faculty of Pharmacy, Cairo University, Egypt. Electronic address: medhat.alghobashy@cu.edu.eg.
authors.forename: Medhat A
authors.initials: MA
authors.lastname: Al-Ghobashy
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Samar F
authors.initials: SF
authors.lastname: Farid
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kassem
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000097:blood* / Q000378:metabolism; D001201:Ascites / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D057230:Limit of Detection; D059625:Liquid-Liquid Extraction / Q000379:methods; D008103:Liver Cirrhosis / Q000188:drug therapy; D008879:Midodrine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D011355:Prodrugs; D008879:Midodrine; C551228:desglymidodrine
keywords: Ascites; Comparative pharmacokinetics; Desglymidodrine; Individualized therapy; LC–MS/MS; Midodrine