Pharmacokinetics of tacrolimus and mycophenolic acid are altered, but recover at different times during hepatic regeneration in rats.
Hepatic regeneration is very critical to the success of living donor liver transplantation, which allows a reduced size liver to grow in size to accommodate the requirements of both the donor and the recipient. The objectives of this study were to evaluate 1) the hepatic metabolism of the two immunosuppressive drugs, tacrolimus and mycophenolic acid (MPA), and 2) the pharmacokinetics of tacrolimus and mycophenolic acid at various time points after initiation of hepatic regeneration by partial hepatectomy in rats. The hepatic intrinsic clearance of tacrolimus was decreased to 70% and 51% of the control level at the 24th h and the 6th day, respectively, but returned to normal level by day 14. The total body clearance of tacrolimus was reduced transiently but recovered completely by day 18. The hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th h and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th h but recovered by day 6. The magnitude of reduction in the clearance of tacrolimus and MPA was much smaller than what was predicted from in vitro data. The elimination clearance of MPA glucuronide was also impaired during hepatic regeneration but recovered to normal level with time. In conclusion, the pharmacokinetics of tacrolimus and mycophenolic acid were altered during hepatic regeneration but recovered completely at different rates over time. Caution must be exercised in extrapolating in vitro data to in vivo conditions during hepatic regeneration.
Tian
Hui
H
718 Salk Hall, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA. rv+@pitt.edu
Ou
Junhai
J
Strom
Stephen C
SC
Venkataramanan
Raman
R
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D005965:Glucuronates / Q000096:biosynthesis / Q000097:blood; D020719:Glucuronides; D006498:Hepatectomy; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000097:blood / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D005965:Glucuronates; D020719:Glucuronides; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D012333:RNA, Messenger; D016559:Tacrolimus; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C113145:mycophenolic acid glucuronide; C095122:multidrug resistance protein 3