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Pharmaceutics. 2018 Jul 2;10(3). pii: E79. doi: 10.3390/pharmaceutics10030079.

Simultaneous Determination of Five Cytochrome P450 Probe Substrates and Their Metabolites and Organic Anion Transporting Polypeptide Probe Substrate in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

Heo JK1,2, Kim HJ3,4, Lee GH5,6, Ohk B7,8, Lee S9,10, Song KS11, Song IS12, Liu KH13,14, Yoon YR15,16.

Author information

1
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea. anna4602@gmail.com.
2
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. anna4602@gmail.com.
3
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea. khj110917@nate.com.
4
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. khj110917@nate.com.
5
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea. lgh2710@gmail.com.
6
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. lgh2710@gmail.com.
7
Clinical Trial Center, Kyungpook National University Hospital, Daegu 41566, Korea. dhrqhfka@naver.com.
8
Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, College of Medicine, Kyungpook National University, Daegu 41944, Korea. dhrqhfka@naver.com.
9
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea. sangkyu@knu.ac.kr.
10
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. sangkyu@knu.ac.kr.
11
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. kssong@knu.ac.kr.
12
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. isssong@knu.ac.kr.
13
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea. dstlkh@knu.ac.kr.
14
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea. dstlkh@knu.ac.kr.
15
Clinical Trial Center, Kyungpook National University Hospital, Daegu 41566, Korea. yry@knu.ac.kr.
16
Department of Biomedical Science, BK21 Plus KNU Bio-Medical Convergence Program for Creative Talent, College of Medicine, Kyungpook National University, Daegu 41944, Korea. yry@knu.ac.kr.

Abstract

A rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (P450) probe substrates and their phase I metabolites in human plasma was developed. The OATP1B1 (pitavastatin) and five P450 probe substrates, caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) and their metabolites were extracted from human plasma (50 µL) using methanol. Analytes were separated on a C18 column followed by selected reaction monitoring detection using MS/MS. All analytes were separated simultaneously within a 9 min run time. The developed method was fully validated over the expected clinical concentration range for all analytes tested. The intra- and inter-day precisions for all analytes were lower than 11.3% and 8.82%, respectively, and accuracy was 88.5⁻117.3% and 96.1⁻109.2%, respectively. The lower limit of quantitation was 0.05 ng/mL for dextromethorphan, dextrorphan, midazolam, and 1'-hydroxymidazolam; 0.5 ng/mL for losartan, EXP-3174, omeprazole, 5'-hydroxyomeprazole, and pitavastatin; and 5 ng/mL for caffeine and paraxanthine. The method was successfully used in a pharmacokinetic study in healthy subjects after oral doses of five P450 and OATP1B1 probes. This analytical method provides a simple, sensitive, and accurate tool for the determination of OATP1B1 and five major P450 activities in vivo drug interaction studies.

KEYWORDS:

cytochrome P450; drug interaction; liquid chromatography-tandem mass spectrometry; organic anion transporting polypeptide; pharmacokinetics

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