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.

Application of Modified Michaelis – Menten Equations for Determination of Enzyme Inducing and Inhibiting Drugs

“…The general disposition of a drug is the same of local disposition at various sites in the body, whereas the local disposition is the sum of micro-disposition in the cells. Therefore, understanding of the disposition in vitro and in loci is indispensable in clinical situations (Yamaoka and Takakura, 2004). Botts-Morales theory on catalytic properties of an enzyme is related to allosteric effects, enzymes activated by monovalent cations and cofactorscontrolled protease -zymogen interactions (Di Ceraet al, 1996).…”

Application of modified Michaelis – Menten equations for determination of enzyme inducing and inhibiting drugs

“…The general disposition of a drug is the same of local disposition at various sites in the body, whereas the local disposition is the sum of micro-disposition in the cells. Therefore, understanding of the disposition in vitro and in loci is indispensable in clinical situations [ 69 ]. Botts- Morales theory on catalytic properties of an enzyme is related to allosteric effects [ 70 ].…”

Application of substrate depletion assay for early prediction of nonlinear pharmacokinetics in drug discovery: Assessment of nonlinearity of metoprolol, timolol, and propranolol

“…We further investigated applicability of the substrate depletion assay for quantitatively predicting nonlinearity. Nonlinear pharmacokinetics have been evaluated using several approaches such as population pharmacokinetic analysis and compartment model analysis combined with saturable metabolism 26–29. Analysis was directed toward identification of factors responsible for nonlinear plasma concentrations using the most adaptable model selected, and has aimed to give information on nonlinear pharmacokinetics in animal and clinical investigations.…”