Dose-dependent kinetic

May follow dose-dependent kinetics. Mean t% is 50 hours for 50 mg and 22 hours for 100 mg. 

As a result of saturation of protein binding glucocorticosteroids may exhibit a dose-dependent kinetic behavior with increases of both distribution volume and half-life with increased doses. 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

Liira, J., G. Johanson, and V. Riihimaki. 1990. Dose-dependent kinetics of inhaled methyl ethyl ketone in man. Toxicol. Lett. 50(2-3) 195-201. 

When using such models, it is assumed that the disposition of a chemical is governed by first-order processes. This means that the rate of disappearance of a xenobiotic from the body, as a result of excretion and/or biotransformation, is proportional to the amount of the xenobiotic in the body at that time. In other words, the quantity of a xenobiotic that leaves the body is large when the amount of xenobiotic in the body is large (e.g., immediately after exposure), whereas this quantity is small when the amount in the body is small (e.g., several hours after exposure). Most xenobiotics exhibit this type of behavior, provided that the several biological mechanisms responsible for disposition are not saturated, i.e., not overwhelmed by large concentrations of xenobiotics (see section Dose-Dependent Kinetics). 

Sarrazin E, Hendeles L, Weinberger M, et al. Dose-dependent kinetics for theophylline Observations among ambulatory asthmatic children. J Pediatr 1980 97 825-828. 

PO/SubQ/IV. Only anticoagulant commonly used parenterally. Dose-dependent kinetics. Metabolized in liver to inactive products. 

Weinberger, M. and Ginchansky, E., Dose-dependent kinetics of theophylline disposition in asthmatic children, J. Pediatr, 91(5) 820-824, 1977. 

The plasma clearance, half-life and volume of distribution of prednisolone is reported to be independent in the range of the doses 10, 20 and 30 mg prednisolone adminstered orally (139). Pickup et al (140) studied pharmacokinetics of prednisolone at different levels in ten subjects, four normal subjects and six patients with osteoarthritis after intravenous administration of prednisolone. Average prednisolone half-lives were found to be between 2.6 to 3.8 h, mean volume distribution between 0.22 to 0.64 1/kg, and plasma clearance between 1.02 to 2.0 ml/min/kg following the tracer 0.15 mg/kg and 0.3 mg/kg doses. This data showed sginificant increases in volume of distribution and plasma clearance of prednisolone with inceasing dose. An increase in half-life was also observed. Pickup et al. (140) thus postulate that the observed dose-dependent kinetics is primarily due to the non-linearity in... 

For drugs that exhibit non-linear or dose dependent kinetics, the fundamental pharmacokinetic parameters such as clearance, the apparent volume of distribution and the elimination half life may vary depending on the administered dose. This is because one or more of the kinetic processes (absorption, distribution and/or elimination) of the drug may be occurring via a mechanism other than simple first-order kinetics. For these drugs, therefore, the relationship between the AUC or the plasma concentration at a given time at steady state and the administered dose is not linear (Fig. 15.2). 

Figure 5. Multiple actions of toxin II from Ammonia sulcata (ATX II) on voltage-clamped Na currents (Ij ) from amphibian myelinated nerve. This stabilizer toxin works in a dose-dependent manner to inhibit channel inactivation see bottom panel) and, as a consequence, delay the time of peak current see top panel). The reduction of peak current amplitude does not result directly from these kinetic alterations and is not observed with all stabilizers (Reproduced with permission from Ref. 39. Copyright 1981 SPPIF).

The differences between palytoxin and PDBu with respect to kinetics, temperature dependence, and effect on low affinity binding suggest that these two different types of tumor promoters may be acting through different mechanisms. Further, in contrast to PDBu, the effect of palytoxin is not readily reversible (33). To determine where the two pathways differ, we compared the relative ability of palytoxin and PDBu to inhibit EGF binding in protein kinase C depleted cells. Swiss 3T3 cells were depleted of protein kinase C to different extents by exposing confluent quiescent cells to 0, 20, 200, or 2000 nM PDBu for 72 hr. Previous results indicate that this treatment depletes cells of protein kinase C activity in a dose-dependent manner (31). 

In vitro culture isolated brain cells exposed for 20 h to graded concentrations of nickel chloride up to 116 mg Ni/L DOMESTIC DOG, Canis familiaris Diet Time- and dose-dependent effects on kinetics of brain microtubule polymerization effects reversed on removal of Ni2+ from culture media 4... 

Potency comprises both achon and inhibition of achon and is predicted by the Hill model though a 50% level is chosen, it is an arbitrary percentage and other values such as 60 or 40% action can also be calculated and used. Potency is not a relevant factor xmless it is so low that the dose requirement is very high (to a level where nonlinear binding with albumin can be observed, resulting in nonlinear kinetics) or where the serious side effects are dose-dependent and make an effechve dose unacceptably toxic. The potency, EC50, is expressed in a mechanishc equilibrium model where the achon is direct ... 

After the administration of a drug, its concentration in plasma rises, reaches a peak, and then declines gradually to the starting level, due to the processes of distribution and elimination (p. 46). Plasma concentration at a given point in time depends on the dose administered. Many drugs exhibit a linear relationship between plasma concentration and dose within the therapeutic range (dose-linear kinetics (A) note different scales on ordinate). However, the same does not apply to drugs whose elimination processes are already sufficiently activated at therapeutic plasma levels so as to preclude further proportional increases in the rate of elimination when the concentration is increased further. Under these conditions, a smaller proportion of the dose administered is eliminated per unit of time. 

The time course of the effect and of the concentration in plasma are not identical, because the concentration-effect relationships obeys a hyperbolic function (B cf. also p. 54). This means that the time course of the effect exhibits dose dependence also in the presence of dose-linear kinetics (C). 

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