Accepted Manuscript Title: Simultaneous determination of probe drugs, metabolites, inhibitors and inducer in human plasma by liquid chromatography/tandem mass spectrometry and its application to pharmacokinetic study Author: Kim H. Hee Zhangyan Yao Lawrence S. Lee PII: DOI: Reference:

S0731-7085(13)00431-7 http://dx.doi.org/doi:10.1016/j.jpba.2013.09.006 PBA 9255

To appear in:

Journal of Pharmaceutical and Biomedical Analysis

Received date: Revised date: Accepted date:

19-6-2013 3-9-2013 4-9-2013

Please cite this article as: K.H. Hee, Z. Yao, L.S. Lee, Simultaneous determination of probe drugs, metabolites, inhibitors and inducer in human plasma by liquid chromatography/tandem mass spectrometry and its application to pharmacokinetic study, Journal of Pharmaceutical and Biomedical Analysis (2013), http://dx.doi.org/10.1016/j.jpba.2013.09.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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*Graphical Abstract

We developed a robust analytical LC/MS-MS method to simultaneously quantify probes, inducer and inhibitor of important drug metabolism enzymes shown above.

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*Highlights (for review)

Highlights

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We developed a rapid and sensitive liquid chromatography-mass spectrometry method We simultaneous quantified midazolam, raltegravir and their major metabolites We also quantified rifampicin (inducer), ritonavir and ketoconazole (inhibitors) We applied this method in a clinical study in Singapore to probe CYP3A and UGT1A1

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*Revised Manuscript

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Simultaneous determination of probe drugs, metabolites, inhibitors and inducer in

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human plasma by liquid chromatography/tandem mass spectrometry and its application

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to pharmacokinetic study

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Kim H. Hee1*, Zhangyan Yao1 , Lawrence S. Lee1*

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National University Health System, 1E Kent Ridge Road, Singapore 119228, Singapore

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Lawrence Lee, Assistant Professor, Department of Medicine, National University of

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Singapore, Level 10 NUHS Tower Block, 1E Kent Ridge Road, Singapore 119228, Singapore

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E-mail: [email protected]

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Phone number: + (65) 6779-5555

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Fax number: + (65) 6872-4130

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Short Title: Assay for CYP3A and UGT1A1 probes, inhibitors and inducer

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ABSTRACT

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Cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferase 1A1 (UGT1A1) are

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important enzymes responsible for the metabolism of many xenobiotics. To investigate their

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induction and inhibition properties, administering probe drugs and monitoring their

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concentration in plasma under the effects of inducers/inhibitors is the gold standard method.

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A rapid and sensitive liquid chromatography-tandem mass spectrometry method was

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developed for simultaneous quantification of midazolam, raltegravir (probe drugs for

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CYP3A4

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hydroxymidazolam glucuronide and raltegravir glucuronide, rifampicin (inducer), ritonavir

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and ketoconazole (inhibitors). Analytes were extracted from 100 µl of plasma using solid-

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phase extraction followed by chromatographic separation on a reversed-phase C18 column

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(50 mm x 2.1 mm, particle size 1.8 μm). The mass spectrometer was operated under positive

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ionization mode. Excellent linearity (r2 ≥ 0.995) was achieved for all. The method was

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validated and found to be accurate (88 to 111%), precise (CV%

tandem mass spectrometry and its application to pharmacokinetic study.

Cytochrome P450 3A4 (CYP3A4) and UDP-glucuronosyltransferase 1A1 (UGT1A1) are important enzymes responsible for the metabolism of many xenobiotics. To...
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