TY - JOUR T1 - IN VITRO CHARACTERIZATION OF LAMOTRIGINE <em>N</em>2-GLUCURONIDATION AND THE LAMOTRIGINE-VALPROIC ACID INTERACTION JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1055 LP - 1062 DO - 10.1124/dmd.106.009340 VL - 34 IS - 6 AU - Andrew Rowland AU - David J. Elliot AU - J. Andrew Williams AU - Peter I. Mackenzie AU - Ronald G. Dickinson AU - John O. Miners Y1 - 2006/06/01 UR - http://dmd.aspetjournals.org/content/34/6/1055.abstract N2 - Studies were performed to investigate the UDP-glucuronosyltransferase enzyme(s) responsible for the human liver microsomal N2-glucuronidation of the anticonvulsant drug lamotrigine (LTG) and the mechanistic basis for the LTG-valproic acid (VPA) interaction in vivo. LTG N2-glucuronidation by microsomes from five livers exhibited atypical kinetics, best described by a model comprising the expressions for the Hill (1869 ± 1286 μM, n = 0.65 ± 0.16) and Michaelis-Menten (Km 2234 ± 774 μM) equations. The UGT1A4 inhibitor hecogenin abolished the Michaelis-Menten component, without affecting the Hill component. LTG N2-glucuronidation by recombinant UGT1A4 exhibited Michaelis-Menten kinetics, with a Km of 1558 μM. Although recombinant UGT2B7 exhibited only low activity toward LTG, inhibition by zidovudine and fluconazole and activation by bovine serum albumin (BSA) (2%) strongly suggested that this enzyme was responsible for the Hill component of microsomal LTG N2-glucuronidation. VPA (10 mM) abolished the Hill component of microsomal LTG N2-glucuronidation, without affecting the Michaelis-Menten component or UGT1A4-catalyzed LTG metabolism. Ki values for inhibition of the Hill component of LTG N2-glucuronidation by VPA were 2465 ± 370 μM and 387 ± 12 μM in the absence and presence, respectively, of BSA (2%). Consistent with published data for the effect of fluconazole on zidovudine glucuronidation by human liver microsomal UGT2B7, the Ki value generated in the presence of BSA predicted the magnitude of the LTG-VPA interaction reported in vivo. These data indicate that UGT2B7 and UGT1A4 are responsible for the Hill and Michaelis-Menten components, respectively, of microsomal LTG N2-glucuronidation, and the LTG-VPA interaction in vivo arises from inhibition of UGT2B7. The American Society for Pharmacology and Experimental Therapeutics ER -