Abstract
Tacrolimus (Tacro) is a potent immunosuppressant and a central agent in the prevention of posttransplantation rejection. Tacro is characterized by a narrow therapeutic index and wide interindividual pharmacokinetic fluctuation. The contribution of human UDP-glucuronosyltransferase (UGT) 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 16 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 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 varied among individuals (6.4-fold variation; n = 16), and common nonsynonymous variants may contribute to this variability. In the human embryonic kidney 293 cellular model, no significant differences in enzyme kinetics could be revealed for UGT1A4*2 (P24T) and *3 (L48V), whereas the allozyme *4 (R11W) displayed a 2-fold higher velocity (p < 0.01) compared with 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 with homozygote for the reference genotype UGT1A4*1/*1. We conclude that UGT1A4 is the major isoform involved in Tacro glucuronidation, whereas additional studies are required to assess the contribution of UGT1A4 genetic factors in tacrolimus glucuronidation variability.
Footnotes
This work was supported by the Canadian Institutes of Health Research [Grant MOP-89954] (to C.G. and É.L.); and the Canada Research Chair Program (C.G.). I.L. was supported by the Fonds de l'Enseignement et de la Recherche of the Faculty of Pharmacy (Laval University); É.L. is the recipient of a Canadian Institutes of Health Research Clinician Scientist Salary Award (Phase 2); and C.G. is the holder of a Canada Research Chair in Pharmacogenomics.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039040.
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ABBREVIATIONS:
- Tacro
- tacrolimus
- G
- glucuronide
- UGT
- UDP-glucuronosyltransferase
- LTG
- lamotrigine
- AZT
- 3′-azido-3′-detocythymidine
- TFP
- trifluoperazine
- HEK
- human embryonic kidney
- LC
- liquid chromatography.
- Received February 21, 2011.
- Accepted April 12, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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