Identification of cyclosporine A and tacrolimus glucuronidation in human liver and the gastrointestinal tract by a differentially expressed UDP-glucuronosyltransferase: UGT2B7

Background/Aims: The oral administration of the major transplant immunosupp ressants cyclosporine A and tacrolimus leads to unpredictable drug levels r equiring drug monitoring. Hepatic and extrahepatic metabolism of cyclospori ne A and tacrolimus by cytochrome P450 proteins has been analyzed but metab olism and inactivation by glucuronidation has not been investigated. Methods: Cyclosporine A and tacrolimus glucuronidation was measured in hepa tic and gastrointestinal microsomal protein, and with 11 recombinant hepati c and extrahepatic family 1 and 2 UDP-glucuronosyltransferases. UDP-glucuro nosyltransfcrase transcripts were determined by polymerase chain reaction. Results: Significant cyclosporine and tacrolimus glucuronidation activity w as present in endoplasmic reticulum from liver, duodenum, jejunum, ileum an d colon, but was absent in stomach. Specific cyclosporine A glucuronidation activity was highest in liver and colon, tacrolimus glucuronidation was hi ghest in liver, Analyses using recombinant UDP-glucuronosyltransferases ide ntified UGT2B7 as a human UDP-glucuronosyltransferase with specific activit y toward cyclosporine A and tacrolimus. The hepato-gastrointestinal distrib ution of immunosuppressant glucuronidation activity corresponded to the dif ferential expression pattern of UGT2B7 mRNA. Conclusions: This study provides conclusive evidence of hepatic and extrahe patic immunosuppressant glucuronidation by human UGT2B7 which was identifie d to be differentially expressed in the human hepatogastrointestinal tract. Hepatic and extrahepatic glucuronidation may influence the therapeutic eff icacy of transplant immunosuppressants. (C) 2001 European Association for t he Study of the Liver. Published by Elsevier Science B,V. All rights reserv ed.