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Research ArticleArticle

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

Xiao-Mei Zhuang, Yu-Huan Zhong, Wei-Bin Xiao, Hua Li and Chuang Lu
Drug Metabolism and Disposition November 2013, 41 (11) 1914-1922; DOI: https://doi.org/10.1124/dmd.113.053199
Xiao-Mei Zhuang
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Yu-Huan Zhong
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Wei-Bin Xiao
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Hua Li
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Chuang Lu
Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China (X.-M.Z., Y.-H.Z., W.-B.X., H.L.); and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts (C.L.)
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Abstract

Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC50, kinact, and KI values were 10.4 ± 1.4 μM, 0.060 ± 0.002 min−1, and 1.13 ± 0.12 μM for PRN, and 7.1 ± 0.6 μM, 0.10 ± 0.01 min−1, and 1.95 ± 0.31 μM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC50 values of 0.26 ± 0.01 μM and 0.22 ± 0.03 μM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min−1 and 0.40 ± 0.06 μM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug–drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

Footnotes

    • Received June 4, 2013.
    • Accepted August 23, 2013.
  • This research was supported by the Chinese National Science and Technology Major Special Project on Major New Drug Innovation [Grants 2008ZXJ09006001 and 2012ZX09301003001].

  • dx.doi.org/10.1124/dmd.113.053199.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (11)
Drug Metabolism and Disposition
Vol. 41, Issue 11
1 Nov 2013
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Research ArticleArticle

CYP1A2 Inhibition by Psoralen and Isopsoralen

Xiao-Mei Zhuang, Yu-Huan Zhong, Wei-Bin Xiao, Hua Li and Chuang Lu
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1914-1922; DOI: https://doi.org/10.1124/dmd.113.053199

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Research ArticleArticle

CYP1A2 Inhibition by Psoralen and Isopsoralen

Xiao-Mei Zhuang, Yu-Huan Zhong, Wei-Bin Xiao, Hua Li and Chuang Lu
Drug Metabolism and Disposition November 1, 2013, 41 (11) 1914-1922; DOI: https://doi.org/10.1124/dmd.113.053199
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