Physiologically-based pharmacokinetic clearances

Figure 22.1 A. Schema for a physiologically based pharmacokinetic model incorporating absorption in the stomach and intestines and distribntion to various tissues. B. Each organ or tissue type includes representation of perfusion (Q) and drug concentrations entering and leaving the tissue. Fluxes are computed by the product of an appropriate rate law, and permeable surface area accounts for the affinity (e.g., lipophilic drugs absorbing more readily into adipose tissue). Clearance is computed for each tissue based on physiology and is often assumed to be zero for tissues other than the gut, the liver, and the kidneys.

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Russel FG, Wouterse AC, Van Ginneken CA. 1987. Physiologically based pharmacokinetic model for the renal clearance of salicyluric acid and the interaction with phenolsulfon-phthalein in the dog. Drug Metab Dispos 15 695-701. 

Figure 3.2-5. Model structure of a hypothetical physiologically based pharmacokinetic model. Tissue blood flows are shown (Q) along with renal (CIr) and nonrenal (01 0 drug clearance pathways.

As discussed in Chapter 30 and elsewhere (13), interspecies scaling is based upon allometry (an empirical approach) or physiology. Protein pharmacokinetic parameters such as volume of distribution (Pd), elimination half-life (b/2)/ and elimination clearance (CL) have been scaled across species using the standard allometric equation (14) ... 

There are several approaches to pharmacokinetic modelling. These include empirical, compartmental, clearance-based and physiological models. In the latter full physiological models of blood flow to and from all major organs and tissues in the body are considered. Such models can be used to study concentration-time profiles in the individual organs and e. g. in the plasma [57-60]. Further progress in this area may result in better PK predictions in humans [61]... 

The clearance concept has been used in defining the pharmacokinetics of drugs since the mid-1970s. " The elearanee eoneept is based in physiology, where it is used as a measure of renal funetion (ereatinine elear-ance). Creatinine is formed from muscle breakdown at a constant rate, and thus a constant creatinine concentration in plasma results. The magnitude of this concentration is dependent on the elimination rate of ereatinine and the size of the muscle pool (formation rate). By measuring the plasma concentration and the renal excretion of ereatinine, renal clearance can be estimated and thereby kidney function indicated, as ereatinine is mainly filtered into the urine... 

Theophylline is not only characterized by a narrow therapeutic index and distinct relationships between serum concentration and therapeutic and toxic effects, but also by a high interindividual pharmacokinetic variabihty. This variability is predominantly based on a high patient-to-patient variability in the metabolic clearance of theophylline that is confounded by numerous additional physiological, pathophysiological, and enviromnental factors. Intravenous theophylhne (given as aminophyl-line), for example, has been shown to result in considerable variations in serum concentrations among patients despite the same dose, and theophylline dose requirements to maintain serum concentration in the range of 10 to 20 lig/ml varied from 400 to 3200 mg/day. ... 

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