High-sensitivity liquid chromatography–tandem mass spectrometry for the simultaneous determination of five drugs and their cytochrome P450-specific probe metabolites in human plasma

Oh, Kyung-Suk; Park, Su‐Jin; Shinde, Dhananjay; Shin, Jae‐Gook; Kim, Dong-Hyun

doi:10.1016/j.jchromb.2012.03.014

Cited by 43 publications

(37 citation statements)

References 19 publications

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“…The LC-MS/MS the authors used had an LLOQ of 1.5 ng/mL for OME and higher sensitivity and selectivity than authors who used HPLC with UV detection between 3-96 ng/mL [13][14][15][16][17][18][19] . The most relevant LC-MS/MS-based methods have sensitivities of 0.05 ng/mL 23,24 , 0.4 ng/mL 21 , and 1.2 ng/mL 22 , which were slightly lower than those used by the authors of the present study. In all of these studies, the run times were longer, and samples were prepared using LLE or PPT.…”

Section: Discussioncontrasting

confidence: 70%

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Improvement and Validation of a High-Performance Liquid Chromatography in Tandem Mass Spectrometry Method for Monitoring of Omeprazole in Plasma

Wojnicz

García

Román-Martínez

et al. 2015

Therapeutic Drug Monitoring

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Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in:Therapeutic Drug Monitoring 37.3 (2015) Omeprazole (OME) is a proton pump inhibitor (PPI) with 58% bioavailability after single oral dose, presenting large inter-individual variations and significant drug-drug interactions. A simple and rapid liquid chromatography in tandem with mass spectrometry (LC/MS-MS) with solid phase extraction (SPE) and isotope-labelled internal standard (IS) method was developed to monitor the plasma levels of OME for application in pharmacokinetics and drug-drug interactions studies. OME and its IS (OME-D3), were eluted with Zorbax extend C-18 rapid resolution (4.6 mm x 50 mm, 3.5 μm) at 25ºC, under isocratic conditions through a mobile phase consisting of 1 mM ammonium acetate, pH 8.5 (55%), and acetonitrile (ACN, 45%). The flow rate was 0.8 mL/min and the run time of chromatogram was 1.2 min. OME was detected and quantified by LC-MS/MS with positive electrospray ionization (ESI) that operates in multiple-reaction monitoring (MRM) mode. The method was linear in the range of 1.5-2000 ng/mL for OME. The validation assays of accuracy and precision, matrix effect, extraction recovery and stability of the samples for OME did not deviate more than 20% for the lower limit of quantification (LLOQ) and no more than 15% for other quality controls (QCs), according to regulatory agencies. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation AbstractOmeprazole (OME) is a proton pump inhibitor (PPI) with 58% bioavailability after a single oral dose. It is subject to marked inter-individual variations and significant drugdrug interactions. The authors developed a simple and rapid method based on liquid chromatography in tandem with mass spectrometry (LC/MS-MS) with solid phase extraction (SPE) and isotope-labelled internal standard (IS) to monitor plasma levels of OME in pharmacokinetics and drug-drug interaction studies. OME and its IS (OME-D3) were eluted with the Zorbax Extend C-18 rapid resolution column (4.6 mm x 50 mm, 3.5 μm) at 25ºC, under isocratic conditions through a mobile phase consisting of 1 mM ammonium acetate, pH 8.5 (55%), and acetonitrile (ACN, 45%). The flow rate was 0.8 mL/min, and the chromatogram run time was 1.2 min. OME was detected and quantified by LC-MS/MS with positive electrospray ionization (ESI), which operates in multiple-reaction monitoring (MRM) mode. The method was linear in the range of 1.5-2000 ng/mL for OME. The validation assays for accuracy and precision, matrix effect, extraction recovery, and stability of the samples for OME did not deviate more than 20% for the lower limit of quantification (LLOQ) and no more than 15% for other quality controls (QCs). These findings are consistent with the requirements of regulatory agencies.

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Section: Discussioncontrasting

confidence: 70%

“…Our chromatographic run lasted 1.2 min, which is shorter than times recorded elsewhere (>1.3 min 13,15,17,[21][22][23][24] or even >16 min 17 ). The authors used a Zorbax Extend C-18 high-resolution column, which enabled us to work with a high flow of 0.8 mL min and provided a short analysis time.…”

Section: Discussionmentioning

confidence: 77%

Improvement and Validation of a High-Performance Liquid Chromatography in Tandem Mass Spectrometry Method for Monitoring of Omeprazole in Plasma

Wojnicz

García

Román-Martínez

et al. 2015

Therapeutic Drug Monitoring

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“…CYP2D15 is the major CYP2D in dog liver, with enzymatic activities to human CYP2D6 [4]. On the other hand, the AUC 0-24h ratio of dextrorphan/dextromethorphan in dogs is 0.00, different from humans [57]. Dextrorphan are transformed into 3-hydroxymorphinan in part by CYP3A4 in humans [54].…”

Section: Discussionmentioning

confidence: 99%

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

S¹

2015

J Drug Metab Toxicol

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To clarify species differences in the pharmacokinetic parameters of cytochrome P450 (CYP) activities between humans and experimental animals, we assessed several CYP activities in mice, rats, dogs, monkeys, and microminipigs, using the simultaneous administration of typical human CYP substrates, such as caffeine (human CYP1A2 substrate), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A), to these animals. The intrinsic clearance (CL int ) of these 5 substrates was also examined using the liver microsomes of humans and the experimental animals. The high bioavailabilities (BAs) and low CL int values of caffeine in the experimental animals were similar to those in humans. Mice and monkeys had lower BAs and higher CL int values of losartan than those in humans. Mice, rats, and monkeys had lower BAs and higher CL int values of omeprazole than those in humans. The lowest BAs of dextromethorphan were observed in monkeys and microminipigs, and only the CL int in dogs was similar to that in humans. The BA of midazolam in microminipigs only was similar to that in humans, while the CL int values in the other animals were similar to that in humans. These results indicated that in vitro and in vivo experimental data obtained using multiple animals including microminipigs are useful for predicting human pharmacokinetics.

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“…14) In the current study, we administered midazolam at a relatively low dose (10-fold lower than the therapeutic dose), 13) although the other CYP probes were administered at therapeutic doses. Since plasma concentrations of all drugs could be determined 8 h after administration by our method, our protocol would allow further reduction of the other drug doses.…”

Section: Lc-ms/ms Methods Developmentmentioning

confidence: 99%

“…Recently, Oh et al have developed a method involving simultaneous quantitation by LC-MS/MS for CYP probes and their metabolites, which were used in an Inje cocktail. 14) Their report did not provide the procedure for determining the drug concentrations in urine samples. However, the urine concentration of losartan and the ratio of dextromethorphan to dextrorphan in urine were used for in vivo phenotyping of CYP2C9 and CYP2D6, respectively.…”

Section: Lc-ms/ms Methods Developmentmentioning

confidence: 99%

Simultaneous LC-MS/MS Analysis of the Plasma Concentrations of a Cocktail of 5 Cytochrome P450 Substrate Drugs and Their Metabolites

Tanaka

Uchida

Inui

et al. 2014

Biological & Pharmaceutical Bulletin

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A "cocktail" approach, which involves simultaneous administration of multiple CYP-specific probes, concurrently detects the activity of multiple CYP enzymes. We developed and validated a rapid and selective LC-MS/MS method for determining the plasma concentrations of 5 CYP probe drugs and metabolites (caffeine/paraxanthine, CYP1A2 substrate; losartan/losartan carboxylic acid (E3174), CYP2C9 substrate; omeprazole/5-hydroxyomeprazole, CYP2C19 substrate; dextromethorphan/dextrorphan, CYP2D6 substrate; and midazolam/1′-hydroxymidazolam, CYP3A4 substrate) by single-step extraction, followed by a single LC-MS/MS run. An Ostro 96-well plate was used for extraction of CYP substrates and metabolites from human plasma and urine. Following optimization of the chromatographic conditions, all the peaks were well separated, and retention times ranged between 4.4 and 11.7 min. The total run time for a single injection was within 13 min. The accuracy and precision values suggested that the assay had high accuracy and reliability in plasma and urine samples. No significant matrix interference was observed. To demonstrate the efficacy of this method, plasma and urine concentrations of 5 CYP probe substrates and their metabolites were determined after simultaneous oral administration of 5 drugs to 4 healthy volunteers. All the substrates and metabolites were detected over an 8 h period, and the plasma concentrations of each substrate at 8 h after administration were above the lower limit of quantification. Urine concentrations of drugs and their metabolic ratio were evaluated after the administration. In conclusion, the advantage of our cocktail approach is that it enables in vivo assessment of the activity of various drug-metabolizing enzymes in a single assay. Key words cytochrome P450; cocktail; LC-MS/MS; healthy volunteerThe CYP system, which constitutes the major drug-metabolizing machinery in humans, catalyzes the biotransformation of xenobiotics and has been reported to process over 90% of the currently marketed drugs.1,2) The drug-metabolizing activities of different CYP isoforms show high inter-and intraindividual variations; age, gender, genetics, environmental factors, dietary components, and endogenous mediators contribute to this variability. [3][4][5] In addition, certain medications can induce or inhibit the activity of drug-metabolizing enzymes, resulting in drug-drug interactions. Variation in CYP activity results in variation in the pharmacokinetics of its substrates, which in turn may alter the pharmacodynamics of these drugs. Thus, predicting the pharmacokinetics and pharmacodynamics of the drug substrates of CYP is important for predicting potential drug interactions and for CYP substrate dose optimization.A "cocktail" approach concurrently detects the activity of multiple CYP enzymes and involves simultaneous administration of multiple CYP-specific probes followed by the evaluation of their pharmacokinetics in a single experiment. Since the Pittsburgh cocktail was first introduced in 1997, 6) several cocktail...

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High-sensitivity liquid chromatography–tandem mass spectrometry for the simultaneous determination of five drugs and their cytochrome P450-specific probe metabolites in human plasma

Cited by 43 publications

References 19 publications

Improvement and Validation of a High-Performance Liquid Chromatography in Tandem Mass Spectrometry Method for Monitoring of Omeprazole in Plasma

Improvement and Validation of a High-Performance Liquid Chromatography in Tandem Mass Spectrometry Method for Monitoring of Omeprazole in Plasma

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

Simultaneous LC-MS/MS Analysis of the Plasma Concentrations of a Cocktail of 5 Cytochrome P450 Substrate Drugs and Their Metabolites

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