PT  - JOURNAL ARTICLE
AU  - Verawan Uchaipichat
AU  - Peter I. Mackenzie
AU  - David J. Elliot
AU  - John O. Miners
TI  - SELECTIVITY OF SUBSTRATE (TRIFLUOPERAZINE) AND INHIBITOR (AMITRIPTYLINE, ANDROSTERONE, CANRENOIC ACID, HECOGENIN, PHENYLBUTAZONE, QUINIDINE, QUININE, AND SULFINPYRAZONE) “PROBES” FOR HUMAN UDP-GLUCURONOSYLTRANSFERASES
AID  - 10.1124/dmd.105.007369
DP  - 2006 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 449--456
VI  - 34
IP  - 3
4099  - http://dmd.aspetjournals.org/content/34/3/449.short
4100  - http://dmd.aspetjournals.org/content/34/3/449.full
SO  - Drug Metab Dispos2006 Mar 01; 34
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics