Organ clearance modeling

The influences of plasma binding on drug elimination may be best understood by consideration of clearance. All organ clearance models incorporate a proteinbinding term. For example the conversion of the intrin-... 

The simple venous equilibrium model of organ clearance developed by Rowland and Wilkinson can be used to predict the effect of protein binding on hepatic plasma clearance ... 

Recent advances in the field of physiological pharmacokinetics, in which organ blood flows, volumes, and drug clearances are considered, have been useful in estimating drug concentrations in a specific organ. These models have been applied for the most part to antitumor agents. 

Well-stirred model =1 > Underestimate organ clearance for highly extracted drugs... 

The principal organs involved in the peripheral clearance of hGH from the plasma are the kidney and fiver. hGH is cleared via glomerular filtration at the kidney and by a receptor-mediated mechanism at the fiver (58,59). In animal models, derivatives of hGH such as the 20,000 mol wt variant, oligomeric forms, and hGH complexed with GH-binding protein have been shown to be cleared from the semm at significandy lower rates than 22,000 mol wt hGH (60—62). The prolonged plasma half-life of these derivatives probably reflects a combination of decreased receptor affinity and size constraints on glomerular filtration. 

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.

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

Fig. 4. Simplified rearrangement of the pulmonary clearance features of the kinetic model for retention and organ distribution of inhaled mCe.

Clark, K.E., Gobas, F.A.P.C., Mackay, D. (1990) Model of organic chemical uptake and clearance by fish from food and water. Environ. Sci. Technol. 24(8), 1203-1213. 

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]... 

Pharmacokinetics When administered intravenously, ICG rapidly binds to plasma proteins and is exclusively cleared by the liver, and subsequently secreted into the bile [8]. This forms the basis of the use of ICG for monitoring hepatic blood flow and function. Two pharmacokinetics models, a monoexponential decay, which describes the initial rapid clearance of ICG with a half-life of about 3 minutes (Eq. (1)) and a bi-exponential model, which incorporates the secondary phase clearance with a longer half-life (Eq. (2)), describe total clearance of ICG from plasma [ 132]. For real-time measurements by continuous organ function monitoring, the mono-exponential decay is preferred. 

Waller et al. (237) performed a CoMFA study to analyze the metabolic rates of CYP2E1 in rodents as intrinsic clearance of a 12 chlorinated volatile organic compounds (VOCs). After superimposition, the steric and electrostatic field interaction energies, the HINT (/jydropathic interactions) energy (238), and molecular orbital field were calculated in addition to clogP. The best model... 

The Ag cryptate experiments have thus illustrated that the distribution properties in mice peaked immediately after injection with % ID/organ values that were approximately equal to literature values for % CO to those organs. In addition, these studies have shown that the activity in the brain was constant from 1-3 minutes at 0.75% ID/g, consistent with rodent cerebral blood flow (10). This implies that Ag+[2.2.2] crosses the blood brain barrier. Also, modeling of the blood clearance curve showed that Ag+[2.2.2] disproportionated in plasma with a rate constant equal to that which would be expected from the k(j for Ag+[2.2.2] in... 

---