Non-linear pharmacokinetics

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Pharmacokinetic parameters, such as elimination half life (ti/2), the elimination rate constant (K), the apparent volume of distribution (V) and the systemic clearance (Cl) of most drugs are not expected to change when different doses are administered and/or when the drug is administered via different routes as a single or multiple doses. The kinetics of these drugs is described as linear, or dose-independent, pharmacokinetics and is characterized by the first-order process. The term linear simply means that plasma concentration at a given time at steady state and the area under the plasma concentration versus time curve (AUC) will both be directly proportional to the dose administered, as illustrated in Fig. 15.1. 

For some drugs, however, the above situation may not apply. For example, when the daily dose 

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). 

Furthermore, administration of different doses of these drugs may not result in parallel plasma concentration versus time profiles expected for drugs with linear pharmacokinetics (Fig. 15.3). 

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Venlafaxine, although its re-uptake inhibitory activity is not restricted to serotonin, is often classified as an SSRI because of its similar spectrum of adverse reactions. It has a short elimination half-life in contrast to the other serotonin re-uptake inhibitors. Fluoxetine, norfluoxetine and paroxetine are inhibitors of their own metabolism by CYP2D6 resulting in non-linear pharmacokinetic behavior. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

H. Cheng, W. R. Gillespie, and W. J. Jusko. Review article mean residence time concepts for non-linear pharmacokinetic systems. Biopharm. Drug Dispos. 15 627-641, 1994. 

Preclinical Pharmacology. The pharmacokinetics of total and free platinum were determined following oral gavage of JM216 as part of the schedule dependency antitumor experiments described above [20], At doses of 9.5,40 (day 1), 40 (day 5) and 200 mg/kg, non-linear pharmacokinetics were observed, both in terms of total and ultrafilterable platinum. On comparing doses of 9.5 and 40 mg/kg, the AUCs increased by tenfold and out of proportion to the fourfold increase in dose. Conversely, a further fivefold increase in dose to 200 mg/kg (the maximum tolerated for single-dose administration) was accompanied by only a twofold increase in AUC, consistent with saturable absorption. Similar Cmax and AUC values for total and ultra-filterable platinum were obtained on day 5 vs. day 1 for the 40 mg/kg dose level. 

Paroxetine metabolism at low concentrations is dependent on CYP2D6, which is almost saturated at these concentrations, Thus, there are non-linear pharmacokinetics and an increase in the half-life of paroxetine from 10 to 20 hours when the dose is increased from lOmg to 20mg, At higher concentrations, the metabolism is mainly by CYP3A4 isoenzymes, Paroxetine inhibits the activity of CYP2D6 in the lowest usually effective antidepressant dose,... 

Cheng, H. Gillespie, W.R. Jusko, W.J. Mean residence time concepts for non-linear pharmacokinetic systems. Biopharm Drug Dispos. 1994, 15 (8), 627-641. 

Godfrey, K.R. Fitch, W.R. The deterministic identifiability of non-linear pharmacokinetic models. J. Pharmacokin. Biopharm. 1984,12, 177-191. 

Km the first-order rate constant for metabolism of dmg or [in context] the Michaelis constant in non-linear pharmacokinetics Ko the zero-order elimination rate constant Mother the first-order rate constant for elimination of dmg by a process other than metabolism or renal excretion Kio for a two-compartment dmg, the first-order rate constant for elimination of dmg from the central compartment Ki2 for a two-compartment drug, the first-order rate constant for transfer from the central to the peripheral compartment K21 for a two-compartment drug, the first-order rate constant for transfer from the peripheral to the central compartment MAT mean absorption time mean residence time in the gastrointestinal tract synonymous with MRTgit... 

Ritonavir inhibits the cytochrome P450 isoenzyme CYP2D6, which is responsible for the demethylenation of ecstasy, so concurrent use leads to a sharp rise in ecstasy plasma levels. Poor liver function (due to alcoholism) may have been a contributory factor in one patient, and further CYP inhibition by nitric oxide (the metabolite of amyl nitrate) may have contributed to another case. An additional factor is that ecstasy may show non-linear pharmacokinetics. Metamfetamine is also metabolised by CYP2D6 and its levels would therefore similarly be raised by ritonavir. 

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