title: Simultaneous determination of bupropion, metroprolol, midazolam, phenacetin, omeprazole and tolbutamide in rat plasma by UPLC-MS/MS and its application to cytochrome P450 activity study in rats.
abstract: A specific ultra-performance liquid chromatography tandem mass spectrometry method is described for the simultaneous determination of bupropion, metroprolol, midazolam, phenacetin, omeprazole and tolbutamide in rat plasma with diazepam as internal standard, which are the six probe drugs of the six cytochrome P450 isoforms CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19 and CYP2C9. Plasma samples were protein precipitated with acetonitrile. The chromatographic separation was achieved using a UPLC® BEH C18 column (2.1 × 100 mm, 1.7 µm). The mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) with gradient elution. The triple quadrupole mass spectrometric detection was operated by multiple reaction monitoring in positive electrospray ionization. The precisions were <13%, and the accuracy ranged from 93.3 to 110.4%. The extraction efficiency was >90.5%, and the matrix effects ranged from 84.3 to 114.2%. The calibration curves in plasma were linear in the range of 2-2000 ng/mL, with correlation coefficient (r(2) ) >0.995. The method was successfully applied to pharmacokinetic studies of the six probe drugs of the six CYP450 isoforms and used to evaluate the effects of erlotinib on the activities of CYP2B6, CYP2D6, CYP3A4, CYP1A2, CYP2C19 and CYP2C9 in rats. Erlotinib may inhibit the activity of CYP2B6 and CYP3A4, and may induce CYP2C9 of rats.
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, Shanghai, 200063, China.|Analytical and Testing Center of Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Jianshe
authors.initials: J
authors.lastname: Ma
authors.affiliation: The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, 323000, China.
authors.forename: Shuanghu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, Shanghai, 200063, China.|Analytical and Testing Center of Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Shanghai Institute of Pharmaceutical Industry, Shanghai, 200437, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: The Laboratory of Clinical Pharmacy, The People's Hospital of Lishui, Lishui, 323000, China.
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Chongliang
authors.initials: C
authors.lastname: Lin
authors.affiliation: The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
authors.forename: Guanyang
authors.initials: G
authors.lastname: Lin
authors.affiliation: Shanghai Key Laboratory of Forensic Medicine, Institute of Forensic Science, Ministry of Justice, Shanghai, 200063, China.|Analytical and Testing Center of Wenzhou Medical University, Wenzhou, 325035, China.
authors.forename: Xianqin
authors.initials: X
authors.lastname: Wang
mesh_terms: D000759:Adjuvants, Anesthesia / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000097:blood; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000097:blood; D016642:Bupropion / Q000097:blood; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000097:blood; D057230:Limit of Detection; D008297:Male; D008874:Midazolam / Q000097:blood; D009853:Omeprazole / Q000097:blood; D004364:Pharmaceutical Preparations / Q000097:blood*; D010615:Phenacetin / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D054328:Proton Pump Inhibitors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014044:Tolbutamide / Q000097:blood
chemical_list: D000759:Adjuvants, Anesthesia; D018712:Analgesics, Non-Narcotic; D018687:Antidepressive Agents, Second-Generation; D007004:Hypoglycemic Agents; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D054328:Proton Pump Inhibitors; D016642:Bupropion; D003577:Cytochrome P-450 Enzyme System; D014044:Tolbutamide; D000069347:Erlotinib Hydrochloride; D010615:Phenacetin; D009853:Omeprazole; D008874:Midazolam
keywords: CYP450; UPLC-MS/MS; cocktail; erlotinib