Passive diffusion of drugs

Artursson, R, Epithelial transport of drugs in cell culture. I A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells, J. Pharm. Sci. 79, 476-482 (1990). 

First-order input (11). First-order kinetic input (II) delivers drug at a rate proportional to the concentration gradient driving the transfer of drug movement. A classic example of a first-order kinetic process is the passive diffusion of drug across a homogeneous barrier. The differential equation describing first-order kinetic behavior is shown in Eq. (1.13) ... 

Coadministration of a P-gp modulator also does not reduce the bioavailability of P-gp substrates when the passive influx of drug greatly exceeds the rate of efflux by P-gp. For instance when therapeutic doses of indinavir are administered intestinal lumen concentrations of this protease inhibitor far exceed its Kin for P-gp-mediated efflux (80 81). Therefore it is likely that indinavir saturates intestinal P-gp at these concentrations and passive diffusion of drug through enterocytes exceeds P-gp-mediated efflux. 

Key factors influencing the passive diffusion of drugs across the BBB are lipid solubility and molecular size. The relationship is described by the equation D = log P/MS /2, where D is diffusion, log P is lipophilicity, and MS is molecular size. Thus, improving the passive diffusion of drugs across the BBB can be accomplished by either increasing lipophilicity or reducing molecular size. As lipophilicity is dependent on polarity and ionization, modification and/or masking of... 

From an in vitro perspective, solubility in water and in organic solvents determines the choice of solvent, which, in turn, influences the choice of extraction procedure and analytical method. Solubility can also indirecfly impact the timeframe of an assay for compounds that are unstable in solution. From an in vivo perspective, the solubility of a compound influences its absorption, distribution, metabolism, and excretion. Both water solubility and lipid solubility are necessary for the absorption of orally administered antimicrobial drugs from the gastrointestinal tract. This is an important consideration when selecting a pharmaceutical salt during formulation development. Lipid solubility is necessary for passive diffusion of drugs in the distributive phase, whereas water solubility is critical for the excretion of antimicrobial drugs and/or their metabolites by the kidneys. 

Pathological barriers such as abscesses impede the passive diffusion of drugs. 

A simple apparatus has been designed for measuring the passive diffusion of drugs through an artificial lecithin membrane. It is claimed that this model system gives results similar to those obtained with natural Type 1 membranes (Misra, Hunger and Keberle, 1966). Other work with artificial membranes is outlined in Chapter 14. 

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