TY - JOUR
T1 - Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats
T2 - Evaluation of protein binding effects using the modeling and simulation approach
AU - Yoshimura, Kazuaki
AU - Yano, Ikuko
AU - Kawanishi, Misaki
AU - Nakagawa, Shunsaku
AU - Yonezawa, Atsushi
AU - Matsubara, Kazuo
N1 - Funding Information:
This study was supported in part by JSPS KAKENHI number 25460210.
Publisher Copyright:
© 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia.
AB - This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia.
KW - Inosine-5-monophosphate dehydrogenase
KW - Mycophenolic acid
KW - Nagase analbuminemic rat
KW - Nonlinear mixed effects modeling
KW - UDP-Glucuronosyltransferase
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U2 - 10.1016/j.dmpk.2015.10.004
DO - 10.1016/j.dmpk.2015.10.004
M3 - Article
C2 - 26643991
AN - SCOPUS:84958773357
SN - 1347-4367
VL - 30
SP - 441
EP - 448
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 6
ER -