Biophase distribution model

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

Biophase Distribution Model. Drug distribution to the effect site may represent a rate-limiting step for drugs in exerting their pharmacological effect. Holford and Sheiner introduced a hypothetical effect-compartment (Fig. 7), and proposed that a drug must first enter this effect compartment from either the central or the peripheral pharmacokinetic compartment before its pharmacological response is exerted. ... 

Danhof, M., de Jongh, J., De Lange, E. C., Della Pasqua, O., Ploeger, B. A., Voskuyl, R. A. Mechanism-based pharmacokinetic-pharmacodynamic modeling biophase distribution, receptor theory, and dynamical systems analysis. Anna Rev Pharmacol Toxicol 2007,47 357-400. 

This temporal displacement may be related to a slow biophase distribution process between plasma and effect concentrations, and the specific mechanism of drug action, such as an indirect effect or a signal transduction process. Several models that have been developed to account for this phenomenon are discussed below. 

Danhof, M. et al., Mechanism-based pharmacokinetic-pharmacodynamic modeling Biophase distribution, receptor theory, and dynamical systems analysis. Annu. Rev. 

Fig. 14. Schematic description of pharmacokinetic and pharmacodynamic determinants of drug action. Distribution from the measurement site (Cp) to the biophase (Ce), determined by a distribution rate constant is followed by drug-induced inhibition or stimulation of the production (k ) or removal (A out) of a mediator (R), transduction of the response R and further transformation of R to the measured effect E, if the measured effect variable is not R. (Modified from Jusko WJ, Ko HC, Ebling WF. Convergence of direct and indirect pharmacodynamic response models. J Pharmacokinet Biopharm 1995 23 5-6.)...

In the rat, the observed effects of oral LD50 reflect both the intrinsic toxicity at the ultimate biophase site of action and the factors influencing distribution, membrane transport, protein binding, metabolism and excretion. The manifestation of acute mammalian toxicity is hence a much more complex response than can be described with the use of log alone, although individual processes such as bioavailability and adsorption depend on lipophilic-ity. The fit to a common QSAR model requires that each of these processes has similar structural dependences, qualitatively and quantitatively, within a given class of compounds. If a different process becomes predominant (i.e. rate limiting), the structure-toxicity relationship must alter thus the compound will be an outlier even when the principal mechanism of intrinsic toxicity remains the same. 

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