RESUMEN
Macromolecules (substitutive enzymes, polymeric prodrugs, immunotoxins, radiolabeled antibodies, or peptide hormones) are of interest in the treatment of several diseases. To reach the tissues, these macromolecular drugs have to cross the capillary wall, which represents an important transfer limitation. While pharmacokinetics usually studies the changes in drug concentration in different body compartments, analyzing the amount of drug gaining access to its target may be more relevant for assessing the efficiency of macromolecules than for low molecular mass drugs. To determine the influence of different parameters on the fraction of the injected dose gaining access to the pharmacologic target, we constructed pharmacokinetic models where two uptakes, both linear or nonlinear, work either in the same compartment (no transport limitation), or in compartments separated by a transport barrier. Numerical applications were carried out with parameters obtained either experimentally or from the literature. We conclude that it is of little use to increase the affinity (K(uptake)) of a macromolecular drug for its target when a transport limitation and an undesired elimination from the plasma space are both present. Likewise, an increase of the uptake (rate of uptake or maximal velocity) by the target is not very productive because permeability of the capillary wall is the factor limiting access of macromolecules to tissues. Maximal efficiency of therapeutic macromolecules could be achieved by increasing, where feasible, the transport across the barrier between the plasma and the target, and by preventing the undesired eliminations as much as possible.
Asunto(s)
Sustancias Macromoleculares , Farmacocinética , Animales , Permeabilidad Capilar , Glucosa Oxidasa/metabolismo , Humanos , Inyecciones Intravenosas , Ratones , Modelos Biológicos , RatasRESUMEN
This paper discusses interacting diffusion and reaction in an open enzyme system. The enzyme, rabbit muscle phosphofructokinase (PFK; ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11), is inhibited strongly by excess of the substrate ATP. Metabolites diffuse through an inert membrane separating the enzyme from the bulk reacting medium. We demonstrate that such a simple system is able to account for the existence of both oscillatory behavior (limit cycle) and multiple steady states (hysteresis) as well as for the sudden transitions between stable and periodic behaviors. Experimental evidence for time oscillations is given.
Asunto(s)
Músculos/enzimología , Fosfofructoquinasa-1/metabolismo , Adenosina Trifosfato/farmacología , Animales , Compartimento Celular , Cinética , Matemática , Fosfofructoquinasa-1/antagonistas & inhibidores , ConejosRESUMEN
The analysis of an allosteric model for phosphofructokinase, exhibiting an inhibition by excess substrate (ATP) shows the possibility of sustained self-oscillations. This model is described by a system of, two ordinary differential equations taking into account the coupling between metabolites diffusion (Fick's first law) and enzyme reaction. The different behavior types of the system have been studied as a function of two main parameters, rho (ration between respective permeabilities for ATP and F6P) and sigma (valuation of the diffusional constraints importance). The research for instability conditions has been carried out by normal mode analysis.
Asunto(s)
Fosfofructoquinasa-1/metabolismo , Animales , Glucólisis , Cinética , Modelos Biológicos , ConejosRESUMEN
Hysteresis, oscillations, and pattern formation in realistic biochemical systems governed by P.D.E.s are considered from both numerical and mathematical points of view. Analysis of multiple steady states in the case of hysteresis, and bifurcation theory in the cases of oscillations and pattern formation, account for the observed numerical results. The possibility to realize these systems experimentally is their main interest, thus bringing further arguments in favor of theories explaining basic biological phenomena by diffusion and reaction.