title: Analysis methods and recent advances in nonlinear pharmacokinetics from in vitro through in loci to in vivo.
abstract: An attempt has been made to review the nonlinearities in the disposition in vitro, in situ, in loci and in vivo mainly from a theoretical point of view. Parallel Michaelis-Menten and linear (first-order) eliminations are often observed in the cellular uptake, metabolism and efflux of drugs. The well-stirred and parallel-tube models are mainly adopted under steady-state conditions in perfusion experiments, whereas distribution, tank-in-series and dispersion models are often used under nonsteady-state conditions with a pulse input. The analysis of the nonlinear local disposition in loci is reviewed from two points of view, namely an indirect method involving physiologically based pharmacokinetics (PBPK) and a direct (two or three samplings) method using live animals. The nonlinear global pharmacokinetics in vivo is reviewed with regard to absorption, elimination (metabolism and excretion) and distribution.
authors.affiliation: Department of Biopharmaceutics and Drug Metabolism, School of Graduate Pharmaceutical Science, Kyoto University, Japan. yamoaka@pharm.kyoto-u.ac.jp
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D002478:Cells, Cultured; D007408:Intestinal Absorption; D017711:Nonlinear Dynamics; D010599:Pharmacokinetics; D014018:Tissue Distribution