Nonlinear disposition

Model simulations showed that the fractions of the body burden contained in the liver and adipose tissue vary nonlinearly as a function of the overall body concentration this was in agreement with published data in rodents, monkeys and humans. The authors further modeled the disposition kinetics of CDDs in liver, adipose tissue, and whole body as a function of time (Carrier et al. 1995b). The results showed that the rate of change in CDD tissue concentrations varies as a function of total body burden such that whole body elimination rate decreases as body burden decreases, suggesting nonlinear disposition kinetics. 

Theorem 16.8. Disposition Decomposition of Nonlinear Disposition with Linear Distribution Kinetics The drug concentration response, c(t), resulting from a bolus input of a drug with a linear distribution kinetics can be decomposed as follows ... 

In addition to their simple and meaningful interpretation, the above RTCs have the distinct advantage that they are dose independent for linear disposition kinetics and nonlinear disposition kinetics as long as the nonlinearity is limited to a nonlinear central elimination. The RTC parameters above are simply related to the drug s volume of distribution, V, and volume of distribution at steady state... 

Ferrero, J.L., Thomas, S.B., Marsh, K.C., Rodrigues, A.D., Uchic, J.T. and Buko, A.M. (2002) Implication of P450-metabolite complex formation in the nonlinear pharmacokinetics and metabolic fate of ( )-(l R, 3R )-3-phenyl-l-[(l, 2, 3, 4 -tetrahydro-5, 6 -methylene-dioxy-l -naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in dogs. Drug Metabolism and Disposition, 30 (10), 1094-1101. 

Absorption/Distribution - Propafenone is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration. It exhibits extensive first-pass metabolism resulting in a dose-dependent and dosage-form-dependent absolute bioavailability. Propafenone follows a nonlinear pharmacokinetic disposition presumably due to saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. 

Metabolism/Excretion - There are 2 genetically determined patterns of propafenone metabolism. In more than 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life of 2 to 10 hours. These patients metabolize propafenone into two active metabolites 5-hydroxypropafenone and N-depropylpropafenone. They both are usually present in concentrations less than 20% of propafenone. The saturable hydroxylation pathway is responsible for the nonlinear pharmacokinetic disposition. 

Compound [ Au(PTA)3 2 Au2(iso-MNT) 2] (Figure 2.51a) is an example of unsupported gold-gold interactions. It has been prepared from the water soluble [AuCl (PTA)3] and K2[iso-MNT] [286] and its crystal structure consists on a nonlinear tetranudear chain. A cydic disposition of the four gold atoms is found in [Au4(S2CMe)4] (Figure 2.51b) [287]. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five different patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. (Modified, with permission, from Jusko WJ Bioavailability and disposition kinetics of phenytoin in man. In Kellaway P, Peterson I [editors]. Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)... 

Target-mediated drug disposition is often associated with nonlinearity in the pharmacokinetics of the affected drug, as the elimination pathway mediated via... 

A mechanism-based PK/PD model for rHu-EPO was used to capture the physiological knowledge of the biological system. An open, two-compartment disposition model with parallel linear and nonlinear clearance, and endogenous EPO at baseline, was used to describe recombinant human erythropoietin (rHu-EPO) disposition after intravenous administration [35]. The pharmacodynamic effect of rHu-... 

P. Veng-Pedersen, Theorems and implications of a model independent elimination/distri-bution function decomposition of linear and some nonlinear drug dispositions. I. Derivations and theoretical analysis. / Pharmacokinet Biopharm 12 627-648 (1984). 

In a structured modeling context, linear drug disposition is commonly thought of as a disposition governed by first-order processes. Contrary to this, the LSA approach defines linear disposition independently of the structure of the disposition processes (distribution and elimination). Linear disposition is simply a linear relationship (L) between input (7) and the measured systemic drug concentration, C. A so-called nonlinear absorption is sometimes observed in oral administrations when... 

In contrast to other modeling approaches, the disposition decomposition technique enables the elimination kinetics to be isolated and determined nonparametrically without the need for a specific structured modeling of the distribution kinetics. Such objective determination of the nonlinear elimination kinetics is of significant value in the areas of nonlinear drug level predictions and absorption evaluations. Moreover, the nonparametric determination provides a useful visualization of the nonlinear elimination kinetics that may be quite helpful in determining the mechanism of the elimination process. 

Richard, 1., Cardot, J. M., and Godbillon, J., Stable isotope methodology for studying the performance of metoprolol Oros tablets in comparison to conventional and slow release formulations, Eur. J. Drug Metab. Pharmacokinet., 19 375-380, 1994. Veng-Pedersen, R, Theorems and implications of a model independent elimina-tion/distribution function decomposition of linear and some nonlinear drug dispositions. 1. Derivations and theoretical analysis, J. Pharmacokinet. Biopharm., 12 627-648, 1984. 

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