title: Plasma protein binding, pharmacokinetics, tissue distribution and CYP450 biotransformation studies of fidarestat by ultra high performance liquid chromatography-high resolution mass spectrometry.
abstract: Fidarestat, an aldose reductase inhibitor, has been used for the treatment of the diabetic associated complications such as retinopathy, neuropathy and nephropathy. To better understand the metabolism and pharmacokinetics of fidarestat, we have evaluated plasma protein binding, pharmacokinetics, tissue distribution of the drug and its conjugated metabolites and CYP450 biotransformation by liquid chromatography-high resolution mass spectrometry. Effective chromatographic separation of fidarestat and hydrochlorothiazide (IS) in rat plasma and tissues was achieved on Hypersil gold C-18 column in an isocratic elution mode. For detection, a high-resolution Orbitrap mass spectrometer with heated electrospray ionization inlet in the negative ion mode was used. High-resolution extracted ion chromatograms for each analyte were obtained by processing the full-scan MS mode with 5 ppm mass tolerance. The impact of plasma protein binding with the drug and conjugated metabolites of the drug on pharmacokinetics has been determined. The study indicated that 9.5% of free form of fidarestat may be pharmacologically active and the Cmax for free fidarestat was found to be 80.30 ± 6.78 ng/mL. The AUC0-t and AUC0-∞ were found to be 185.46 ± 32 and 195.92 ± 15.06 ng h/mL, respectively. Among tissues, the maximum observed distribution was found to be in kidney followed by liver and heart. Docking experiments and in vitro CYP450 reaction phenotyping revealed that two CYP1A2 and CYP2D6 are involved in the phase I metabolism of fidarestat. Oxidative deamination and N/O glucuronidation are the major phase I and phase II metabolites, respectively. In vitro CYP450 inhibition assay of fidarestat for drug-drug interaction showed weak inhibition and may not alter pharmacokinetics, distribution or clearance of other co-administered drug.
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical, Technology, Hyderabad 500 007, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
authors.forename: Murali Mohan
authors.initials: MM
authors.lastname: Bhandi
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500 037, India.
authors.forename: Ajay P
authors.initials: AP
authors.lastname: Dubey
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160 062, Punjab, India.
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandekar
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160 062, Punjab, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical, Technology, Hyderabad 500 007, India. Electronic address: banerjees74@hotmail.com.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500 037, India. Electronic address: srini@iict.res.in.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
mesh_terms: D000818:Animals; D001711:Biotransformation / Q000502:physiology; D001798:Blood Proteins / Q000032:analysis / Q000378:metabolism*; D002853:Chromatography, Liquid / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D005260:Female; D048289:Imidazolidines / Q000032:analysis / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D001798:Blood Proteins; D048289:Imidazolidines; C077139:fidarestat; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; Drug–drug interaction; Drug–herb interaction; Protein binding; UPLC/ESI/HRMS method