Kinetics clearance-limited

Limited data are available on the pharmacokinetics of arecoline. Intravenously administered arecoline in subjects with Alzheimer s disease shows variation in the optimal dose (between 4 and 16 mg/day) due to differing plasma kinetics (Asthana et al. 1996). The mean plasma half-lives for these doses were 0.95 0.54 and 9.3 4.5 minutes, respectively. However, the mean plasma concentrations that optimized cognitive effects were 0.31 0.14 ng/ml. Drug clearance was 13.6 5.8 L/min and the volume of distribution was 205 170 L. 

Since it is beyond the scope of this article to treat the subject of target vulnerability in any detail, the interested reader (with proper security clearance) is recommended to Ref 3. This handbook as a whole does not consider chemical, biological or nuclear weapons. It is intentionally limited to kinetic energy or explosive energy type weapons. A synopsis of the contents by chapter follows ... 

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. 

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). 

It is accepted that the kinetics of myocardial protein appearance in the circulation depends on infarct perfusion. Early reperfusion causes an earlier increase above the upper reference limit and an earlier and greater enzyme peak after reperfusion. However, once the peak has occurred, there is no difference in the time of clearance of enzymes. In addition, enhanced washout identifies whether an artery is patent or closed but cannot distinguish between nor-... 

In addition to the well-stirred model that is the basis for Equation 7.6, several other kinetic models of hepatic clearance have been developed (4). However, the following discussion will be based on the relationships defined by Equation 7.6, and the limiting cases represented by Equations 7.7 and 7.8. 

The most common approach to in vivo pharmacokinetic and pharmacodynamic modeling involves sequential analysis of the concentration versus time and effect versus time data, such that the kinetic model provides an independent variable, such as concentration, driving the dynamics. Only in limited situations could it be anticipated that the effect influences the kinetics, for example effects on blood flow or drug clearance itself. 

Oxidative Biotransformation in Microsomes The rapid determination of pharmacokinetic parameters, solubility, permeability, and in vitro stability in plasma or liver tissue can often provide a reasonable explanation of the mechanisms limiting oral bioavailability. An approach that is often used is to extrapolate the in vitro rate of metabolism to estimate the hepatic clearance using in vitro-in vivo correlation methods.82-86 These methods use in vitro kinetic parameters, usually Vmllx/Km or in vitro t ji, to determine the intrinsic clearance, which is then scaled to hepatic clearance using the amount of tissue in the in vitro incubation, the weight of the liver, and the well-stirred model for hepatic clearance. 

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]. 

It has been shown that free cholesterol molecules can transfer between membranes by diffusion through the intervening aqueous layer [17], Desorption of free cholesterol molecules from the donor lipid-water interface is rate-limiting for the overall transfer process and the rate of this step is influenced by interactions of free cholesterol molecules with neighboring phospholipid molecules. The influence of phospholipid unsaturation and sphingomyelin content on the rate of free cholesterol exchange are known in pure phospholipid bilayers and similar effects probably occur in cell membranes. The rate of free cholesterol clearance from cells is determined by the structure of the plasma membrane [17] It follows that the physical state of free cholesterol in the plasma membrane is important for the kinetics of cholesterol clearance and cell cholesterol homeostasis, as well as the structure of the plasma membrane. 

Information seems to be limited to these few reports and with the exception of one case report, they all found that proton pump inhibitors reduced the clearance of methotrexate. Any changes in methotrexate kinetics are important in terms of the potential for increased toxicity. Further study is required. The authors of one study in which the levels of methotrexate and its active metabolite were increased during the concurrent use of omeprazole or lansoprazole advise against concurrent use. Further, the authors of one report recommend that if omeprazole is necessary for a patient about to receive methotrexate, then omeprazole should be discontinued 4 to 5 days before methotrexate administration. The situation with other proton pump inhibitors may be similar. Ranitidine was found to be a suitable alternative in two of the cases.Note that the risks would appear to be most significant with high-dose methotrexate, but the case report involving a 15 mg weekly dose of methotrexate introduces a note of caution in all patients. 

The semilogarithmic plot is resolved into components by the method of subtraction, and the half-time (fi/2) of each component is determined graphically. The rate of efflux of labeled solute (k, %/min) is calculated from k = 0.693/fi/2 x 100 (Cutler et al., 1971). This method reveals a fast component for amino acids, as well as other compounds of different molecular weight. It has a ty2 of 2-3 mm in tissue slices for all components studied and probably represents the washout of adherent medium. The slow component is the loss of isotope from the tissue as a whole it is different for different substances and is sensitive to temperature changes The apparent first order kinetics of the slow component does not preclude the possibility that the amino acids are lost from different tissue compartments at different rates. This does, however, suggest that the loss from one major compartment to another may be rate-limiting for clearance from the whole tissue (Cutler et al., 1971). In brain slices, the slow exponential loss of amino acids is linear throughout 40 min of superfusion, and at the end of this time, 60-70% of the labeled amino acids are recovered in the effluent (Cutler et al., 1971)... 

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