Capacity-limited clearance

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 ... 

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). 

High-clearance drugs are those for which there is no saturation of the reaction that converts the drug, and therefore, the clearance rate approaches the blood-flow rate. For capacity-limited drugs, flow rate is irrelevant, and clearance is a simple product of the unbound fraction and the intrinsic clearance. 

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. 

When the volume of the compartment being cleared is constant, the assumption that the fractional flow rate is constant is equivalent to assuming that the clearance is constant. But in the general case, in which the volume of distribution cannot be assumed constant, the use of the fractional flow rates k is unsuitable, because the magnitude of k depends as much upon the volume of the compartment as it does upon the effectiveness of the process of removal. In contrast, the clearance depends only upon the overall effectiveness of removal, and can be used to characterize any process of removal whether it be constant or changing, capacity-limited or supply-limited [308]. 

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... 

Capacity-Limited Metabolism For some drugs clearance changes with the drug concentration. Increases in maintenance doses will result in a disproportionate increase in the steady-state drug concentration. Phenytoin is the classic capacity-limited drug. 

Saturation of metabolism (capacity-limited metabolism) Phenytoin and ethanol saturate hepatic metabolism, showing decreased hepatic clearance with increased dose. 

When single doses of 100, 200, 400, 600, 800, and 1200 mg of clarithromycin were compared in healthy subjects, the pharmacokinetics of the parent drug and metabolite were nonlinear [51], with apparent capacity-limited formation of the 14-(i )-hydroxy metabolite at doses of >600 mg. Nonlinear kinetics were also seen in studies of single and multiple doses of clarithromycin, where increases in C ,ax and AUC of the parent drug were more than proportionate with the dosages [52]. In another study, the AUC for clarithromycin increased 13-fold, with a 4.8-fold increase in dose. Pharmacokinetic data suggest that nonlinearity was due predominantly to a decrease in the apparent metabolic clearance, which fell from 913 to 289 ml/min (Table II) [50]. 

Straight-Lobe Type This type is illustrated in Fig. 10-79. Such units are available for pressure differentials up to about 83 kPa (12 Ibf/in ) and capacities up to 2.549 X lO mvh (15,000 ftVmin). Sometimes multipfe units are operated in series to produce higher pressures individual-stage pressure differentials are limited by the shaft deflection, which must necessarily be kept small to maintain rotor and casing clearance. 

TWo-Teeth Difference. In this type of pump an abutment on one side plate is used to fill the clearance between the external and internal gear. This construction reduces leakage but involves the use of an overhung internal gear. Such a gear arrangement limits the application of these pumps to small and moderate-volume capacity pumps. 

---