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Development of a simultaneous LC-MS/MS method to predict in vivo drug-drug interaction in mice.
Jo, Jung Jae; Jo, Jun Hyun; Kim, SunJoo; Lee, Jae-Mok; Lee, Sangkyu.
Affiliation
  • Jo JJ; BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • Jo JH; BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • Kim S; BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
  • Lee JM; Department of Periodontology, School of Dentistry, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940, Republic of Korea. leejm@knu.ac.kr.
  • Lee S; BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea. sangkyu@knu.ac.kr.
Arch Pharm Res ; 41(4): 450-458, 2018 Apr.
Article in En | MEDLINE | ID: mdl-29550976
Cocktail substrates are useful in investigating drug-drug interactions (DDI) that can rapidly identify the cytochrome P450 (CYP) isoforms that interact with test drugs. In this study, we developed and validated five probe drugs for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A using LC-MS/MS to determine CYP activities in mice. The five probe substrates were caffeine (2 mg/kg), bupropion (30 mg/kg), omeprazole (4 mg/kg), dextromethorphan (40 mg/kg), and midazolam (2 mg/kg) for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A, respectively. The cocktail substrates were orally administered to male 5-week-old ICR mice over 0-240 min. The analytical method was validated; it showed high selectivity, linearity, and acceptable accuracy. We confirmed the lack of interaction of this cocktail in the control state (no effect of CYP inducer or inhibitor) and suggested AUCratio (metabolite/substrate) as a unit to evaluate DDI in vivo. In addition, the cocktail assay was applied for the determination of pharmacokinetic parameters against phenobarbital as a selective CYP2B inducer and ketoconazole as a strong CYP3A inhibitor. The concentration of cocktail substrates and the LC-MS/MS method were optimized. In conclusion, we developed a simultaneous and comprehensive analysis system for predicting potential DDI in mice.
Subject(s)
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Interactions / Tandem Mass Spectrometry / Cytochrome P-450 Enzyme Inducers / Cytochrome P-450 CYP3A Inhibitors Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals Language: En Journal: Arch Pharm Res Year: 2018 Document type: Article Country of publication: Corea del Sur

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Drug Interactions / Tandem Mass Spectrometry / Cytochrome P-450 Enzyme Inducers / Cytochrome P-450 CYP3A Inhibitors Type of study: Prognostic_studies / Risk_factors_studies Limits: Animals Language: En Journal: Arch Pharm Res Year: 2018 Document type: Article Country of publication: Corea del Sur