Drug flux

After dialysis, often a rebound is seen in concentrations since elimination from plasma is faster than drug flux from tissue to plasma (Crebound — Ctissue - C). The concentration in plasma follows a bi-exponential kinetics during hemodialysis whereas the concentration in tissue follows mono-exponential kinetics. 

A biologically important factor affecting drug absorption is drug metabolism or reaction coincident with diffusion across a membrane. The reaction often produces inactive or less potent products than the parent drug. It is conceivable that the reaction will also reduce the drug flux into the systemic circulation. We are interested in the effect of reaction on membrane diffusion. 

Golden GM, MvKie JE, Potss RO (1987) Role of stratum comeum lipid fluidity in transdermal drug flux. J Pharm Sci 76 25-28. 

The major pathway of drug transport across buccal mucosa seems to follow simple Fickian diffusion [17]. Passive diffusion occurs in accordance with the pH-partition theory. Considerable evidence also exists in the literature regarding the presence of carrier-mediated transport in the buccal mucosa [18,19]. Examination of Eq. (1) for drug flux,... 

Figure 13.7. Schematic representation of drug flux across a barrier (e.g., cell or synthetic membranes).

It is therefore more sensible (and probably easier and safer) to perform constant current iontophoresis, and this is by far the most common approach. In this case, the power supply adapts the voltage imposed to the resistance of the circuit to keep the intensity of current (and hence the drug flux) constant. Drug transport can now be modeled with Faraday s equation, which links current intensity to ionic flux. 

Transport numbers can be measured by different methods. The small mono- and divalent inorganic ions have been used to demonstrate skin permselectivity, and have been determined from membrane potential measurements, or by the Hittorf method [10,25,77,79]. The latter method has been frequently used for drugs alternatively, the transport number can be estimated from the slope of a plot of drug flux as a function of current intensity (Figure 14.4) [18,66]. 

Application of this model to published data on the iontophoresis of lidocaine [32,78] in the binary system lidocaine-sodium shows a good agreement between experiment and prediction (Figure 14.5). On the other hand, discrepancies have been found for ropinirole [66] in this case, parallel increments in the concentrations of the drug and sodium were undertaken to maintain their molar fractions constant. While Equation 14.8 predicts that the drug flux should remain constant under these circumstances, ropinirole flux actually decreased as the sodium concentration increased. Clearly, further research is required to optimize the form of this model. 

Faraday s law indicates that electromigrative flux increases proportionally with the intensity of current applied. Figure 14.4 shows that the ropinirole hydrochloride transport number can be estimated from the linear relationship between drug flux and applied current [18,66]. The... 

FIGURE 14.6 Iontophoretic fluxes (mean SD, n > 4) of the cationic drug propranolol, and of the electroosmotic marker mannitol, as a function of propranolol concentration in the anode solution. It is observed that (a) drug flux does not increase linearly with increasing concentration, and (b) electroosmosis is significantly impeded with increasing propranolol concentration. (Data from Marro, D. et al., Pharm. Res., 18 (12), 1701, 2001.)... 

Finally, it is worth reiterating that transport numbers are relatively complex functions of the concentration and mobility of all the ions present in the system. Thus, while the relationship between lidocaine molar fraction in the binary system (lidocaine-sodium) and the drug flux has been well defined [32,78], the results cannot be directly extrapolated to a different anodal composition. That is, the drug flux depends not only on its molar fraction [59], but also on the mobilities of the competing ions [115]. 

Achievement of a sufficient input flux of drug. The achievement of sufficient input drug flux is probably the greatest challenge to designing a successful controlled release delivery system. While some controlled... 

The automatic flow-through diffusion cell system described is designed to allow the rapid analysis of drug flux through human skin in vitro with minimum variability. 

Figure 4.16 Illustration of conversion of pH oscillations to oscillations in drug flux across a lipophilic membrane. Reprinted from [96] with permission from Wiley-Liss Inc., a subsidiary of John Wiley and Sons, Inc.

Schaeffer, H. E., Brietfelter, J. M., and Krohn, D. L. (1982), Lectin-mediated attachment of liposomes to cornea Influence on transcorneal drug flux, Invest. Ophthalmol. Vis. Sci., 23,530-533. 

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