%0 Journal Article %A Isabelle Laverdiere %A Patrick Caron %A Mario Harvey %A Eric Levesque %A Chantal Guillemette %T In vitro investigation of human UDP-glucuronosyltransferase isoforms responsible for tacrolimus glucuronidation: predominant contribution of UGT1A4. %D 2011 %R 10.1124/dmd.111.039040 %J Drug Metabolism and Disposition %P dmd.111.039040 %X Tacrolimus (Tacro) is a potent immunosuppressant and a central agent in prevention of post-transplantation rejection. Tacro is characterized by a narrow therapeutic index and wide interindividual pharmacokinetic fluctuation. The contribution of human UDP-glucuronosyltransferase in its metabolism has not been extensively studied. In vitro metabolism studies support that the liver produced Tacro-glucuronide (Tacro-G) while its formation was minimal or undetectable in the presence of intestine and kidney microsomes. Among 17 human UGTs tested, UGT1A4 was the sole enzyme involved in Tacro-G formation. This conclusion is supported by the finding of inhibition with a specific substrate of UGT1A4 lamotrigine with Ki values highly similar for both human liver and UGT1A4 microsomes and the correlation with trifluoperazine-glucuronide formation by liver microsomes (rs=0.551; p=0.02). Formation of Tacro-G by liver samples was variable between individuals (6.4-fold variation; n=16) and common non-synonymous variants may contribute to this variability. In the HEK293 cellular model, no significant differences in enzyme kinetics could be revealed for UGT1A4*2 (P24T) and *3 (L48V) while the allozyme *4 (R11W) displayed a 2-fold higher velocity (p<0.01) compared to the UGT1A4*1 enzyme preparation. In human liver samples, carriers of the UGT1A4 variants did not display statistically different efficiency in Tacro-G formation compared to homozygote for the reference genotype UGT1A4*1/*1. We conclude that UGT1A4 is the major isoform involved in Tacro glucuronidation while additional studies are required to assess the contribution of UGT1A4 genetic factors in tacrolimus glucuronidation variability. %U https://dmd.aspetjournals.org/content/dmd/early/2011/04/12/dmd.111.039040.full.pdf