Drug transport simulation

Dearden, J. C. Townsend, M. S., Digital computer simulation of the drug transport process, in Proc. 2nd Symp. Chemical Structure-Biological Activity Relationships Quantitative Approaches (Suhl), Akademie-Verlag, Berlin, 1978, pp. 387-393. 

The direct transport of absorbed drugs into systemic circulation, effectively by-passing the first-pass effect of the liver and gastrointestinal tract Lower enzymatic activity compared to the gastrointestinal tract or liver Amenability to self-medication, which increases patient compliance Possibility of pulsatile delivery of some drugs to simulate the biorhythmic release of these drugs Lower risk of overdosage Achievement of controlled release... 

Figure 2 A simulation of drug transport through various aqueous and membrane phases— using the (wrong) assumption that the product of the rate constants of drug transport, kx and k2 (compare Eqs. (28) and (29)), is equal to one—generated a curve that can be approximated by a parabola. (From Ref. 53.)...

The bilinear model is confirmed by simulations, using experimental rate constants of drug transport, which were determined from the time dependence of substance concentrations in the different phases of a three-compartment system water/n-octanol/water (Figure 15) [443]. 

Model simulations (see chapter 4.4) substantiate that the lipophilicity dependence of the rate constants of drug transport should follow bilinear relationships [41,156, 175,345,440,442]. Indeed, bilinear equations have been derived for the rate constants of drug transport in n-octanol/water (eqs. 95 — 98, chapter 4.4) [444 —447] and for the rate constants of the transfer of various barbiturates (38) in a Sartorius absorption simulator from an aqueous phase (pH = 3) through an organic membrane to another aqueous phase (pH = 7.5), modeling the gastric absorption of these compounds (Figure 41) (eq. 162 recalculated optimum log P value) [442]. 

Poirier A, Lave T, Portmann R, Brun M-E, Senner F, Kansy M, Grimm H-P, and Funk C (2008) Design, data analysis, and simulation of in vitro drug transport kinetic experiments using a mechanistic in vitro model. Drug Metab Dispos 36 2434-2444. 

An alternative to the parabolic model is the bilinear model (equation 6) which was derived from computer simulations, using experimental rate constants of drug transport in simple in vitro systems. " In most cases it describes nonlinear lipophilicity-activity relationships more accurately than the parabolic model. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

The Sartorius Absorption Model (26), which served as the forerunner to the BCS, simulates concomitant release from the dosage form in the GI tract and absorption of the drug through the lipid barrier. The most important features of Sartorius Absorption Model are the two reservoirs for holding different media at 37°C, a diffusion cell with an artificial lipid barrier of known surface area, and a connecting peristaltic pump which aids the transport of the solution or the media from the reservoir to the compartment of the diffusion cell. The set-up is shown in Figures 7a and b. 

Modelling of levels and atmospheric transport of drugs of abuse in the urban environment results from ambient levels of dmgs of abuse within the city could be introduced in dispersion models for simulate atmospheric transport of these substances in urban environments. This methodology can be combined with health population data and other tools such as GIS-based systems in order to generate health-risk maps. 

Figure 13.5. Model of Boddy, adapted from reference [7] (Section 13.3.3). The drug-carrier conjugate (DC) is administered at a rate i c(DC) into the central compartment, which is characterized by a volume of distribution To DC is transported by blood flow Qcr to and from the response (target) compartment, characterized by a volume of distribution Vr, and by blood flow Qct to and from the toxicity compartment, characterized by a volume of distribution VV- DC is eliminated from only the central compartment with a clearance CLc(DC). The active drug (D) is released from DC in the central, response and toxicity compartments with first-order rate constants kc, k and fcr> respectively. The D is distributed over these compartments in a manner similar to the DC. The D is eliminated from these compartments with a clearance of CLc(D), CLr(D) and CLt(D), respectively. Conventional drug administration can be simulated by the input of D at a rate i c(D) into the central compartment.

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