Pharmacokinetics of Tacrolimus and Mycophenolic Acid Are Altered, but Recover at Different Times During Hepatic Regeneration in Rats

Abstract

ABSTRACT: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.

Immunosuppression using the mTOR inhibition mechanism affects replacement of rat liver with transplanted cells

“…This strategy helped avoid confounding by perturbation of initial cell engraftment or potential alterations in drug handling, because the pharmacokinetics of immunosuppressive drugs was normal 2 weeks after PH. 20 Liver repopulation in rats treated with Tacro alone, MMF alone, or Tacro plus MMF was 28 Ϯ 6%, 25 Ϯ 3%, and 24 Ϯ 5%, respectively, and this was similar to untreated controls (Fig. 7).…”

Activity and Expression of Various Isoforms of Uridine Diphosphate Glucuronosyltransferase are Differentially Regulated During Hepatic Regeneration in Rats

“…Finally, although the activity and expression of CYPs and UGTs are altered during hepatic regeneration, in general, the recovery of UGT activity seems to be more rapid than the recovery of CYP3A activity as measured by the metabolism and clearance of tacrolimus and mycophenolic acid (17).…”

“…Liver microsomes were prepared by differential centrifugation procedure as per Tian et al (17). The protein content was determined by Lowry's method using bovine serum albumin as the standard (18).…”

Pharmacokinetics of diclofenac in rats intoxicated with CCL4, and in the regenerating liver

“…It is necessary to study how to use them carefully, including their effect on hepatic regeneration and function after hepatic injury. There are reports on the pharmacokinetics of tacrolimus, mycophenolic acids [25] and antipyrine [26] on various conditions of liver damage. In both cases, the pharmacokinetics were altered.…”