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Dosed tissue concentration, calculation

PK models (Section 13.2.4), PD models (Section 13.2.5), and PK/PD models (Section 13.2.6) can be used in two different ways, that is, in simulations (Section 13.2.7) and in data analysis (Section 13.2.8). Simulations can be performed if the model structure and its underlying parameter values are known. In fact, for any arbitrary dose or dosing schedule the drug concentration profile in each part of the model can be calculated. The quantitative measures of the effectiveness of drug targeting (Section 13.4) can also be evaluated. If actual measurements have been performed in in-vivo experiments in laboratory animals or man, the relevant model structure and its parameter values can be assessed by analysis of plasma disappearance curves, excretion rate profiles, tissue concentration data, and so forth (Section 13.2.8). [Pg.338]

FIGURE 2.5 Siimilation of plasma (solid line) and tissue (heavy dashed line) digoxin concentrations after intravenous administration of a 0.75-mg loading dose to a 70-kg patient with normal renal function. Cq is estimated by back extrapolation (dotted line) of elimination-phase plasma concentrations. is calculated by dividing the administered drug dose by this estimate of Cq, as shown. Tissue concentrations are referenced to the apparent distribution volume of a peripheral compartment that represents tissue distribution. (Reproduced with permission from Atkinson AJ Jr, Kushner W. Annu Rev Pharmacol Toxicol 1979 19 105-27.)... [Pg.14]

A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. [Pg.288]

No modern studies of the human pharmacokinetics of LSD have been done, largely because human experimentation has virtually stopped. An older study that used a spectrofluorometric technique for measuring plasma concentrations of LSD was done in humans given doses of 2 Mg/kg i.v. After equilibration had occurred in about 30 min, the plasma level was between 6 and 7 ng/ml. Subsequently, plasma levels gradually fell until only a small amount of LSD was present after 8 hr. The half-life of the drug in humans was calculated to be 175 min (2). Subsequent pharmacokinetic analysis of these data indicated that plasma concentrations of LSD were explained by a two-compartment open model. Performance scores were highly correlated with concentration in the tissue (outer) compartment, which was calculated at 11.5% of body weight. The new estimation of half-life for loss of LSD from plasma, based on this model, was 103 min (47). [Pg.141]

The principal application of PBPK models is in the prediction of the target tissue dose of the toxic parent chemical or its reactive metabolite. Use of the target tissue dose of the toxic moiety of a chemical in risk assessment calculations provides a better basis of relating to the observed toxic effects than the external or exposure concentration of the parent chemical. Because PBPK models facilitate the prediction of target tissue dose for various exposure scenarios, routes, doses, and species, they can help reduce the uncertainty associated with the conventional extrapolation approaches. Direct application of modeling includes... [Pg.732]

The term clearance is used here in the sense of total body clearance and is analogous to the term renal clearance. The body as a whole is regarded as acting as a xenobiotic-eliminating system, where the rate of elimination divided by the average plasma concentration of the compound is the total body clearance. Here clearance is calculated (25) by dividing the administered dose of the substance by the area under the plasma concentrationtime curve produced by that dose. This pharmacokinetic parameter, as well as others presented in this publication, was calculated by the use of the MLAB on-line computer system established at the National Institutes of Health by Knott and Reece (26). Similar to t the total clearance is a composite of the individual clearances of the material by the various tissues of the body. [Pg.249]

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. [Pg.80]

The Drug Delivery Index (DDI) ahows a quantification of the reduction in the drug dose and the systemic exposure observed after drug release specificahy to the colon [37]. It may be calculated using AUC (Area l/nder the plasma drug concentration-time Curve) data or drug concentrations in blood and colonic tissues under steady-state conditions ... [Pg.163]

Poorly perfused tissues (adipose tissue, connective tissue, and bone) require hours to come into equilibrium with plasma drug concentrations (Fig. 25.1). Since the accumulation of anesthetic in body fat is relatively small soon after its IV administration, it is common clinical practice to calculate drug dosage on the basis of lean body mass rather than on total body weight. Thus, an obese patient may receive the same dose of IV anesthetic as a patient of normal body weight. [Pg.293]

The elimination half-times from blood and several tissues were determined in rats administered a single intraperitoneal dose of 10 mg/kg FireMaster BP-6 (Miceli and Marks 1981). Elimination from serum followed first-order kinetics, and a half-time of 23.1 weeks was calculated over a 36-week period after dosing. Adrenal and adipose tissue had the highest PBB concentrations at week 6, and these levels were maintained throughout the 36-week observation period. Concentrations of PBBs were also elevated in the liver, lungs, and pituitary at week 6, whereas PBB levels in brain, kidney, and spleen were several-fold lower. Elimination half-times from adrenal, brain, fat, liver, lung, and spleen were 43.3, 63.0, 69.3, 11.5,... [Pg.207]


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