Qzi

Appendix 1: Recent Studies Reported in Literature (Continued)

MDCKmonolayer-passivetransport-Pgp: The commonly used approximate formula for the passive permeability coefficient is Tran et al. (2004) based on the initial rate of permeation across cell monolayers, requires measurement during the linear phase of permeation, and is not applicable when there is significant back flux of compound or mass balance problem. To develop a rigorous equation that can be used at any time point, that is, that is, valid outside of the linear phase, the mass action equations were integrated for a standard single-barrier model of passive permeability. The simple analytical solution found also allows correction for both loss of drug (e.g., due to binding and/or hydrolysis) and sampling volume loss for multiple time point experiments. To test this equation, we measured the passive permeation of three well-characterized drugs (amprenavir, quinidine, and loperamide) across confluent monolayers of MDCKII-hMDR1 cells. The potent Pgp inhibitor, GF120918, was used to inhibit Pgp activity, and so only passive permeability was determined. Dramatically different time-dependent behavior was observed for the three compounds, with loperamide showing significant loss of compound, and loperamide and quinidine causing plasma membrane modifications over time. The simple and exact equation for the permeability coefficient developed here works from start of transport to equilibrium, being valid when the commonly used approximate equation may not be. Thus, the exact equation is safer to use in any context, even for single time point estimates in HT permeability assays.

Membrane-coated fiber (MCF)-lipophilic transport: A polymer membrane coated onto a section of inert fiber was used as a Xia et al. (2004) permeation membrane in the MCF technique. When MCFs were immersed into a donor solution, the compounds in the solution partitioned into the membrane. At a given permeation time, a fiber was removed from the solution and transferred into a gas chromatography injector for quantitative analysis. The permeation process of a given chemical from the donor phase into the membrane was described by a one-compartment model by assuming first-order kinetics. A mathematical model was obtained that describes the cumulative amount of a chemical permeated into the membrane as a function of the permeation time in an exponential equation. Two constants were introduced into the compartment model that were clearly defined by the physiochemical parameters of the system (a kinetic parameter and the equilibrium absorption amount), and were obtained by regression of the experimental data sampled over a limited time before equilibrium. This model adequately described the permeation kinetics of the MCF technique. All theoretical predictions were supported by the experimental results. The experimental data correlated well with the mathematical regression results. The partition coefficients, initial permeation rate, uptake, and elimination rate constants were calculated from the two constants. The compartment model can describe the absorption kinetics of the MCF technique. The regression method based on the model is a useful tool for the determination of the partition coefficients of lipophilic compounds when it takes too long for them to reach permeation equilibrium. The kinetic parameter and the initial permeation rate are unique parameters of the MCF technique that could be used in the development of quantitative structure-activity relationship (QSAR) models.

Membrane lipoid-polysiloxane-permeation: Through the use of permeation/lipophilicity correlations, the mechanisms of permeation of selected test compounds across artificial lipoidal membranes of the polysiloxane type, in the absence and in the presence of a nonionic surfactant (Polysorbate 80), are investigated, in order to design "in vitro" conditions and features suitable for reproducing "in vivo" intestinal absorption tests, as well as to validate some conclusions arising from "in situ" rat gut experiments about the effects of the synthetic surfactants on drug and xenobiotic absorption processes. Six 4-alkylanilines showing a perfect homology were used as test compounds. The reported results clearly show that the in situ biophysical absorption (diffusion) models are completely reproduced by in vitro tests, provided that perfect sink conditions are achieved. Further selection of artificial membrane polarity should be necessary, however, in order to exactly equalize in vitro and in situ permeation rates. As far as the synthetic surfactant action on permeability is concerned, our conclusions are similar to those drawn from in situ studies, except that the effect of the surfactant on membrane polarity is much smaller and the micelle-solubilizing effect is somewhat larger. The disruption of the aqueous stagnant diffusion layers adjacent to the membranes by the surfactant has been conclusively demonstrated. A clear first-element deviation for aniline, which prevents its inclusion as a term of the tested series, has been observed; this feature should be borne in mind whenever any in vivo/in vitro correlation has to be established.

Membrane-chitosan/tetra ethyl ortho silicate (TEOS)-permeation: A novel organic-inorganic composite membrane was prepared, using TEOS as an inorganic material and chitosan as an organic compound. Equilibrium and oscillatory swelling studies were conducted to investigate swelling behaviors of the membrane according to the pH of the swelling medium. Drug permeation experiments were also performed in phosphate buffer solution of the pH of 2.5 and 7.5, respectively. Lidocaine HCI, sodium salicylate, and 4-acetamidophenol were selected as model drugs to examine the effect of ionic property of drug on the permeation behavior. The effects of membrane composition and the external pH on the swelling and the drug permeation behavior of interpenetrating polymer networks (IPN) membrane could be summarized as follows, chitosan incorporated into TEOS IPN swelled at pH 2.5 while it shrunk at pH 7.5. This swelling behavior was completely reversible and the membrane responded rapidly to the change in environmental pH condition. According to the swelling behavior, an increase in pH from 2.5 to 7.5 yielded an increase in the rate of drug permeation because of the shrinking of the incorporated chitosan in TEOS IPN, while decrease in pH resulted in a low permeation rate. The optimal TEOS-chitosan ratio for maximum pH sensitivity existed and drug permeation was influenced not only with the external pH, but also with the ionic interactions between the drug and membrane.

Membrane-filter immobilized-permeability-botanical: The assessment of transport properties of 23 drugs and natural product molecules was made by using the in vitro model based on filter-IAM, assembled from phosphatidylcholine in dodecane, in buffer solutions at pH 7.4. Five of the compounds were lactones extracted from the roots of the kava-kava plant. Experiments were designed to test the effects of stirring (0-600 rpm) during assays and the effects of varying the assay times (2-15 hr).

Perez-Buendia et al. (1993)

Avdeef et al. (2001)

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