Capacity-limited elimination

In chickens a pattern similar to a capacity limited-elimination was noticed. The cause may be either a capacity limitation in the SDM metabolism (hydroxylation ) of SDM or extensive drug reabsorption from the cloaca occurring at night(known as chrono-pharma-cokinetics). In the chicken, 58 % of the intravenously administered dose is lost, which is also reported for other birds (24). Thus birds must possess additional metabolic pathways. 

For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved (Table 3-1). Capacity-limited elimination is also known as saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. 

Mean clearance (CL) values for cetuximab are displayed as a function of dose in Fig. 14.3. Mean CL values decreased from 0.079 to 0.018 L/h/m2 after single cetuximab doses of 20 to 500 mg/m2, respectively. In the dose range 20 to 200 mg/m2, CL values decreased with dose. At doses of 200 mg/m2 and greater, CL values leveled off at a value of approximately 0.02 L/h/m2. This biphasic behavior suggests the existence of two elimination pathways. The elimination of cetuximab apparently involves a specific, capacity-limited elimination process that is saturable at therapeutic concentrations, in parallel with a nonspecific first-order elimination process that is non-saturable at therapeutic concentrations. Increasing doses of cetuximab will therefore ultimately lead to the saturation of the elimination process that is capacity-limited and that follows Michaelis-Menten kinetics, whereas the first-order process will become the dominant mechanism of elimination beyond a particular dose range. 

Fig. 9. Semilogarithmic plots of plasma concentrations versus time for 3 doses of salicylate administered to the same subject, illustrating capacity-limited elimination. At low plasma concentrations, parallel straight lines are obtained from which the first-order elimination rate constant can be estimated. As long as concentrations remain sufficiently high to saturate the process, elimination follows zero-order kinetics (C. A. M. van Ginneken et al., J. Pharmacokinet. Biopharm., 1974,2, 395-415).

Several drugs, including salicylate (in overdose), alcohol, and possibly some hydrazines and other drugs which are metabolised by acetylation, have saturable elimination kinetics, but the only significant clinical example is phenytoin. With this drug, capacity-limited elimination is complicated further by its low therapeutic index. A 50% increase in the dose of phenytoin can result in a 600% increase in the steady-state blood concentration, and thus expose the patient to potential toxicity. Capacity-limited pathways of elimination lead to plasma concentrations of drugs which can be described by a form of the Michaelis-Menten equation. In such cases, the plasma concentration at steady state is given by... 

This biotransformation process takes place principally in the liver, i.e. in the smooth endoplasmic reticulum, partly also in the mitochondria. The kidneys, lungs, intestine, muscles, spleen and skin are involved to a lesser degree in biotransformation. Through hydrolysis and reduction, the intestinal flora may also play a role in this metabolic process. Biotransformation is limited by the hepatic blood flow (= flow-limited elimination) and by the capacity of microsomal enzyme systems (= capacity-limited elimination). (80, 95)... 

Dosage Levels for Metabolism and Toxicology Studies. Administration of doses above those which saturate metabolic systems or the capacity-limited elimination rate in the test species can cause toxic effects which do not occur at lower dosage levels. This saturation can be the most sensitive indicator of overdosing and should be taken into consideration in choosing the Maximum Tolerated Dose (MTD) for toxicity studies. Toxicological effects generated in overdosed animals may simply be artifacts from which valid extrapolations to potential effects in humans cannot be made. 

Only a subset of the parameter values in the O Flaherfy model require inputs from the user to simulate blood and tissue lead concentrations. Lead-related parameters for which values can be entered into the model include fractional absorption from the gastrointestinal tract partition coefficients for lead in nonbone tissues and in the surface region of bone maximum capacity and half-saturation concentration for capacity-limited binding in the erythrocyte elimination clearance fractional clearance of lead from plasma into forming bone and the restricted permeability coefficients for lead diffusion within bone, from plasma into bone, and from bone into plasma (O Flaherty 1991a). 

In calves and cows at high dose levels (100 SDM mg/kg), a biphasic elimination SDM plasma concentration-time curve was observed with a steady state plasma SCH2OH concentration resulting from the capacity limited hydroxylation of SDM into the latter. The drug concentrations in the milk reflected those in plasma. 

Metabolism/Excretion - Phenytoin is metabolized in the liver and excreted in the urine. The metabolism of phenytoin is capacity-limited and shows saturability. Elimination is exponential (first-order) at plasma concentrations less than 10 mcg/mL, and plasma half-life ranges from 6 to 24 hours. 

Renal failure will result in a diminished elimination of drugs that are primarily secreted, such as penicillins and aminoglycosides, and therefore in a longer half-life of the drug (45). Likewise, liver disease may result in a capacity-limited biotransformation, and consequently in a slower elimination of the drug. Bacterial pneumonia in calves may also result in increased serum oxytetracycline concentrations, a condition that can cause prolonged elimination (46). 

The Weibull distribution allows noninteger shape parameter values, and the kinetic profile is similar to that obtained by the Erlang distribution for p, > 1. When 0 < p < 1, the kinetic profile presents a log-convex form and the hazard rate decreases monotonically. This may be the consequence of some saturated clearance mechanisms that have limited capacity to eliminate the molecules from the compartment. Whatever the value of p, all profiles have common ordinates, p(l/X) = exp(-l). 

Other pathways will continue to operate but, for plasma concentrations of the order of K, an apparently linear decrease in concentration with time will be seen. Thus, for alcohol in healthy adult males, has an average value of 82 lig/ml, and an average value of 202 qg/ml/hour. About 90% of alcohol elimination is usually by the capacity-limited alcohol dehydrogenase (oxidative) pathway, the remainder being by the kidneys and other routes of excretion. The renal clearance of alcohol depends on urine flow, and is approximately equal to urine flow rate, i.e. about 1 ml/min only a trace is eliminated via the lungs. For blood-alcohol concentrations of 100, 350, 1000, and 3500 qg/ml, the elimination of alcohol will be as shown in Table 3. As the concentration rises, so the elimination rate increases (but not proportionately) to reach a value of approximately V... 

Disposition in the Body. Slowly but almost completely absorbed after oral administration the rate of absorption is variable, being prolonged after large doses, and the bioavailability may vary considerably between different formulations. Aromatic hydroxylation is the major metabolic pathway and about 50 to 70% of a dose may be excreted as free or conjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in 24 hours the excretion of this metabolite is dose-dependent and decreases as the dose is increased. Phenytoin hydroxylation is capacity-limited, and is therefore readily inhibited by agents which compete for its metabolic pathways. Less than 5% of a dose is excreted as unchanged drug. Minor metabolites include 5-(3-hydroxyphenyl)-5-phenylhydantoin, 3,4-dihydro-3,4-dihydroxy-phenytoin, catechol, and 3-D-methylcatechol. Up to about 15% of a dose may be eliminated in the faeces. 

Phenytoin. Phenytoin (l s slowly absorbed from the small intestine. The rate, extent, and bioavailability vary because of the manufacturer s formulation process. Intramuscular injection tends to precipitate at the site of injection, resulting in erratic plasma levels these levels are significantly lower than those obtained by the oral route. Phenytoin is metabolized in the liver to inactive hydroxylated metabolites (see Fig. 6.3) (20). For a complete discussion, the reader is referred to the earlier edition of this chapter (8).The metabolism of phenytoin is capacity limited and shows satu-rability. Because the elimination of the p-hy-dro glucuronide metabolite is rate limited by its formation from phenytoin, measure-... 

The clearance of several macromolecules may be characterized using simple linear first-order elimination as shown in Equation (3.2-18) [53,57], but may depend on the animal species and range of dose levels being evaluated. In contrast, many peptide and protein drugs demonstrate saturable or capacity-limited clearance, and CL in Equation (3.2-18) may be defined with a concentration-dependent function, such as ... 

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