| Title: | In vitroand in vivo investigation of metabolic fate of riociguat by HPLC-Q-TOF/MS/MS and in silico evaluation of the metabolites by ADMET predictor() |
| Author(s): | Tiwari SS; Chavan BB; Kushwah BS; Yerra NV; Mukesh S; Sangamwar AT; Thaota JR; Talluri M; |
| Address: | "Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, 500 037, India. Analytical Chemistry and Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500607, India. National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India. Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education & Research, IDPL R&D Campus, Balanagar, Hyderabad, 500 037, India. Electronic address: narendra@niperhyd.ac.in" |
| DOI: | 10.1016/j.jpba.2018.10.050 |
| ISSN/ISBN: | 1873-264X (Electronic) 0731-7085 (Linking) |
| Abstract: | "Riociguat, a guanyl cyclase inhibitor, is one of its kind drug regimen approved for management of pulmonary arterial hypertension and chronic thromboembolism pulmonary hypertension. Extensive literature review indicates lack of comprehensive reports on its metabolic fate. The present study reports the in vivo and in vitro identification and characterization of metabolites of riociguat, using high-performance liquid chromatography-quadruple time-of-flight tandem mass spectrometry. In vitro studies were conducted by incubating the drug in human and rat liver microsomes in presence of respective cofactors. In vivo studies were undertaken by oral administration of suspension of drug to male Sprague-Dawley rats followed by collection of urine, feces and blood at specific intervals. A total of 18 metabolites were observed in in vivo and in vitro matrices which includes hydroxyl, N-oxide, desmethyl, defluorinated hydroxyl, glucuronides and N-acetyl cysteine conjugates. Presence of N-acetyl cysteine conjugates strongly points towards the formation of a reactive metabolite intermediate trapped through N-acetyl cysteine and can be considered a matter of concern as the reactive metabolites have been known to manifest toxicities. Their presence was mimicked in in vitro samples as well. The toxicological properties of drug and metabolites were evaluated by using ADMET Predictor () software" |
| Keywords: | "Acetylcysteine/chemistry Administration, Oral Animals Antihypertensive Agents/administration & dosage/*analysis/metabolism/toxicity Biotransformation Chromatography, High Pressure Liquid/instrumentation/methods Computer Simulation Data Mining Guanylate Cy;" |
| Notes: | "MedlineTiwari, Shristy S Chavan, Balasaheb B Kushwah, Bhoopendra S Yerra, Naga Veera Mukesh, Sumit Sangamwar, Abhay T Thaota, Jagadeshwar Reddy Talluri, M V N Kumar eng England 2018/11/10 J Pharm Biomed Anal. 2019 Feb 5; 164:326-336. doi: 10.1016/j.jpba.2018.10.050. Epub 2018 Nov 1" |
