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

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 (pita...

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Main Authors: Jae-Kyung Heo, Hyun-Ji Kim, Ga-Hyun Lee, Boram Ohk, Sangkyu Lee, Kyung-Sik Song, Im Sook Song, Kwang-Hyeon Liu, Young-Ran Yoon
Format: Article
Language:English
Published: MDPI AG 2018-07-01
Series:Pharmaceutics
Subjects:
Online Access:http://www.mdpi.com/1999-4923/10/3/79
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spelling doaj-6ce0507f67e948ebbc3784bf8890bcc02020-11-24T21:54:01ZengMDPI AGPharmaceutics1999-49232018-07-011037910.3390/pharmaceutics10030079pharmaceutics10030079Simultaneous 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 SpectrometryJae-Kyung Heo0Hyun-Ji Kim1Ga-Hyun Lee2Boram Ohk3Sangkyu Lee4Kyung-Sik Song5Im Sook Song6Kwang-Hyeon Liu7Young-Ran Yoon8BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaBK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaBK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaClinical Trial Center, Kyungpook National University Hospital, Daegu 41566, KoreaBK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, KoreaBK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaClinical Trial Center, Kyungpook National University Hospital, Daegu 41566, KoreaA 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.http://www.mdpi.com/1999-4923/10/3/79cytochrome P450drug interactionliquid chromatography-tandem mass spectrometryorganic anion transporting polypeptidepharmacokinetics
collection DOAJ
language English
format Article
sources DOAJ
author Jae-Kyung Heo
Hyun-Ji Kim
Ga-Hyun Lee
Boram Ohk
Sangkyu Lee
Kyung-Sik Song
Im Sook Song
Kwang-Hyeon Liu
Young-Ran Yoon
spellingShingle Jae-Kyung Heo
Hyun-Ji Kim
Ga-Hyun Lee
Boram Ohk
Sangkyu Lee
Kyung-Sik Song
Im Sook Song
Kwang-Hyeon Liu
Young-Ran Yoon
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
Pharmaceutics
cytochrome P450
drug interaction
liquid chromatography-tandem mass spectrometry
organic anion transporting polypeptide
pharmacokinetics
author_facet Jae-Kyung Heo
Hyun-Ji Kim
Ga-Hyun Lee
Boram Ohk
Sangkyu Lee
Kyung-Sik Song
Im Sook Song
Kwang-Hyeon Liu
Young-Ran Yoon
author_sort Jae-Kyung Heo
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher MDPI AG
series Pharmaceutics
issn 1999-4923
publishDate 2018-07-01
description 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.
topic cytochrome P450
drug interaction
liquid chromatography-tandem mass spectrometry
organic anion transporting polypeptide
pharmacokinetics
url http://www.mdpi.com/1999-4923/10/3/79
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