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Research ArticleArticle

SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES

Verawan Uchaipichat, Peter I. Mackenzie, David J. Elliot and John O. Miners
Drug Metabolism and Disposition March 2006, 34 (3) 449-456; DOI: https://doi.org/10.1124/dmd.105.007369
Verawan Uchaipichat
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Peter I. Mackenzie
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David J. Elliot
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John O. Miners
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Abstract

Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20–0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 μM) and human liver microsomes (6.1 ± 1.2 μM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 μM). Using phenylbutazone and quinine as “models,” inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335 ± 128 μM and 186 μM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.

Footnotes

  • This work was supported by a grant from the National Health & Medical Research Council of Australia.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.007369.

  • ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; AUC, area under the plasma concentration-time curve; AZT, zidovudine, i.e., 3′-azido-3′-deoxythymidine; fuinc, fraction unbound in incubation mixtures; GAZT, 3′-azido-3′-deoxythymidine 5′-β-d-glucuronide; HEK293, human embryo kidney 293 cells; HLM, human liver microsome; HPLC, high-performance liquid chromatography; 4MU, 4-methylumbelliferone; P450, cytochrome P450; TFP, trifluoperazine; TFPG, trifluoperazine glucuronide; UDPGA, UDP-glucuronic acid.

    • Received September 13, 2005.
    • Accepted December 19, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (3)
Drug Metabolism and Disposition
Vol. 34, Issue 3
1 Mar 2006
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SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES
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Research ArticleArticle

SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES

Verawan Uchaipichat, Peter I. Mackenzie, David J. Elliot and John O. Miners
Drug Metabolism and Disposition March 1, 2006, 34 (3) 449-456; DOI: https://doi.org/10.1124/dmd.105.007369

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Research ArticleArticle

SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES

Verawan Uchaipichat, Peter I. Mackenzie, David J. Elliot and John O. Miners
Drug Metabolism and Disposition March 1, 2006, 34 (3) 449-456; DOI: https://doi.org/10.1124/dmd.105.007369
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