Proteins pharmacokinetic modelling

Stirred tank models have been widely used in pharmaceutical research. They form the basis of the compartmental models of traditional and physiological pharmacokinetics and have also been used to describe drug bioconversion in the liver [1,2], drug absorption from the gastrointestinal tract [3], and the production of recombinant proteins in continuous flow fermenters [4], In this book, a more detailed development of stirred tank models can be found in Chapter 3, in which pharmacokinetic models are discussed by Dr. James Gallo. The conceptual and mathematical simplicity of stirred tank models ensures their continued use in pharmacokinetics and in other systems of pharmaceutical interest in which spatially uniform concentrations exist or can be assumed. 

D Shen, M Gibaldi. Critical evaluation of use of effective protein fractions in developing pharmacokinetic models for drug distribution. J Pharm Sci 63 1698-1702, 1974. 

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. 

The sulfation of phenol and the glucuronidation of its hydroquinone metabolite were measured in human liver cytosols and microsomes, respectively. The rate of phenol sulfation varied between 0.31 and 0.92 nmol/mg protein/min this is slightly higher than the rate for mice (0.46) and lower than that for rats (1.20). The rate of hydroquinone glucuronidation was between 0.10 and 0.28 mnol/mg protein/min, slightly higher than that for rats (0.08) and lower than that for mice (0.22). These enzyme-kinetic data were subsequently used to simulate phenol metabolism in mice, rats and humans in vivo, using a com-partmental pharmacokinetic model with benzene as phenol precursor (Seaton et al., 1995). 

After IV application, peptides and proteins usually follow a biexponential plasma concentration-time profile that can best be described by a two-compart-ment pharmacokinetic model [13]. The central compartment in this model represents primarily the vascular space and the interstitial space of well-perfused organs with permeable capillary walls, especially fiver and kidneys, while the peripheral compartment comprises the interstitial space of poorly perfused tissues such as skin and (inactive) muscle [4]. 

Liu X, Smith BJ, Chen C, et al. Use of a physiologically based pharmacokinetic model to study the time to reach brain equilibrium an experimental analysis of the role of blood-brain barrier permeability, plasma protein binding, and brain tissue binding. J Pharmacol Exp Ther 2005 313(3) 1254—1262. 

Vancomycin is approximately 30 to 55% bound to plasma proteins. Its distribution after intravenous administration proceeds as a biphasic process and is consistent with a two or three compartment model. The half-life of the first distributive phase is approximately 0.4 hour in patients with normal renal function the second distributive phase is approximately 1.6 hours [172]. Consistent with its multicompartment pharmacokinetic modeling, vancomycin is widely distributed and penetrates into many different body fluids and... 

Pharmacokinetic models to describe, as a function of formaldehyde air concentration, the rate of formation of formaldehyde-induced DNA-protein cross links in different regions of the nasal cavity have been developed for rats and monkeys (Casanova et al. 1991 Heck and Casanova 1994). Rates of formation of DNA-protein cross links have been used as a dose surrogate for formaldehyde tissue concentrations in extrapolating exposure-response relationships for nasal tumors in rats to estimate cancer risks for humans (EPA 1991a see Section 2. 4.3). The models assume that rates of cross link formation are proportional to tissue concentration of formaldehyde and include saturable and nonsaturable elimination pathways, and that regional and species differences in cross link formation are primarily dependent on anatomical parameters (e g., minute volume and quantity of nasal mucosa) rather than biochemical parameters. The models were developed with data from studies in which... 

Bevill, R. F. et ah. Disposition of sulfadknethoxine in swine inclusion of protein binding factors in a pharmacokinetic model, J. Pharmacokinet. Biopharm., 10 539-550, 1982. 

Guohua A, Morrie ME. 2012. A physiologically based pharmacokinetic model of mitoxantrone in mice and scale-np to humans a semi-mechanistic model on corporating DNA and protein binding. AAPS J 14 352-354. 

It is important to note that the relationship between protein release rates measured in vitro (as in Fig. 1) and rate of protein delivery to tissues following implantation is not yet known. In fact, local rates of protein delivery are likely to vary with both properties of the polymer matrix and physiology of the implantation site as well as with properties of the protein. Several new techniques, however, permit the analysis of protein release under conditions that closely simulate different tissues in the body (Ra-domsky eta/., 1990 Beaty and Saltzman, 1992). In addition, experimental techniques and pharmacokinetic models appropriate for determining rates of delivery to tissue are being developed (Saltzman and Radomsky, 1991 Sherwood, 1993 Krewson and Saltzman, 1994 Salehi-Had and Saltzman, 1994). 

Pharmacokinetic constants for the absorption and elimination of pralid-oxime have been determined in man83. a pharmacokinetic model for flow, lipid solubility, protein binding and saturation-IImited metabolism of thiopental has permitted the a priori prediction of bodily distribution conslsten with experiment . Imipramine and its metabolites are rapidly distributed in the rat and renally and biliary excreted with enterohepatic circulation . Mathematical models have been established for the pharmacokinetics of neurohypophysial and related peptides . The oral administration of 2,3,5, triiodebenzoic acid in goats and a cow by whole-body radioactivity retention showed a rapid distributive and subsequent exponential elimination phase with the metabolites formed by deiodination . Bishydroxycoumarin shows dose-dependent first order elimination in man but not in other species and has been assigned to dose effects on el imi nation . ... 

Uludag, H., D Augusta, D., Golden, J., Li, J., Timony, G., Riedel, R., and Wozney, J.M. Implantation of recombinant human bone morphogenetic proteins with biomaterial carriers a correlation between protein pharmacokinetics and osteoinduction in the rat ectopic model. /. Biomed. Mater. Res. 50 227-238, 2000. 

A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

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