title: Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: Evaluation of protein binding effects using the modeling and simulation approach.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: yoshimura.kazuaki.52r@st.kyoto-u.ac.jp.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: iyano@kuhp.kyoto-u.ac.jp.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.affiliation: Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: misaki.kawanishi@shionogi.co.jp.
authors.forename: Misaki
authors.initials: M
authors.lastname: Kawanishi
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: nakashun@kuhp.kyoto-u.ac.jp.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: ayone@kuhp.kyoto-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: kmatsuba@kuhp.kyoto-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics; D000818:Animals; D003198:Computer Simulation; D004195:Disease Models, Animal; D016903:Drug Monitoring; D020022:Genetic Predisposition to Disease; D020719:Glucuronides / Q000493:pharmacokinetics; D034141:Hypoalbuminemia / Q000097:blood* / Q000201:enzymology; D007168:IMP Dehydrogenase / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D010641:Phenotype; D011485:Protein Binding; D055647:Rats, Transgenic
chemical_list: D020719:Glucuronides; D007166:Immunosuppressive Agents; C113145:mycophenolic acid glucuronide; D007168:IMP Dehydrogenase; D000118:Acetylglucosaminidase; D009173:Mycophenolic Acid
keywords: Inosine-5ʹ-monophosphate dehydrogenase; Mycophenolic acid; Nagase analbuminemic rat; Nonlinear mixed effects modeling; UDP-Glucuronosyltransferase