Quantitative and Mechanistic Assessment of Model Lipophilic Drugs in Micellar Solutions in the Transport Kinetics Across MDR1-MDCK Cell Monolayers.

An approach to characterizing P-glycoprotein (Pgp) interaction potential for sparingly water-soluble compounds was developed using bidirectional transport kinetics in MDR1-MDCK cell monolayers. Paclitaxel, solubilized in a dilute polysorbate 80 (PS80) micellar solution, was used as a practical example. Although the passage of paclitaxel across the cell monolayer was initially governed by the thermodynamic activity of the micelle-solubilized drug solution, Pgp inhibition was sustained by the thermodynamic activity (i.

Capric Acid Absorption in the Presence of Hydroxypropyl-β-Cyclodextrin in the Rat Ileum using the In Situ Single-Pass Perfusion Technique.

The purpose of the present study was to gain quantitative mechanistic insight into the role cyclodextrin carriers may play in the intestinal absorption of highly lipophilic molecules. The physical model approach was employed to investigate capric acid absorption in the rat ileum using the in situ single-pass method with 2-hydroxypropyl-β-cyclodextrin (HPB) present in the perfusate. Two physical models were examined: the flat surface model in which the intestinal wall was treated as a hollow, smooth, circular cylinder, and the villus model in which the intestinal surface allowed for the presence of villi.

Transport of a lipophilic ionizable permeant (capric acid) across a lipophilic membrane (silicone polymer membrane) from aqueous buffered solutions in the presence of hydroxypropyl-β-cyclodextrin.

The present study describes a physical model approach applicable to understanding the transport of highly lipophilic, ionizable drugs across a lipophilic membrane between two aqueous compartments in the presence of a cyclodextrin in the aqueous phase. Model predictions were compared with experimental results of capric acid (HA) transport across a silicone polymer membrane in the presence and in the absence of 2-hydroxypropyl-β-cyclodextrin (HPB) in the aqueous phase over wide ranges of conditions. Key parameters entering into the physical model calculations were the HA-HPB and the A(-)-HPB binding constants, the unionized and ionized free and the complexed HA species diffusion coefficients, the HA pKa, the HA intrinsic silicone polymer membrane permeability coefficient, and the aqueous boundary layer thickness.

Systematic studies on the paracellular permeation of model permeants and oligonucleotides in the rat small intestine with chenodeoxycholate as enhancer.

The objective of this study was to mechanistically and quantitatively analyze chenodeoxycholate-enhanced paracellular transport of polar permeants and oligonucleotides in the rat jejunum and ileum. Micellar chenodeoxycholate solutions were used to perturbate the tight junctions. Supporting studies included assessment of the aqueous boundary layer (ABL) with ABL-controlled permeants, measurements of the permeability coefficients and fluxes of the bile acid in dilute and micellar concentrations, and determinations of pore sizes with paracellular probes (urea, mannitol, and raffinose).

Biophysical characterization of a large conductance anion channel in hypodermal membranes of the gastrointestinal nematode, Ascaris suum.

Patch-clamp recordings from muscle- and cuticle-facing hypodermal membranes of the gastrointestinal nematode Ascaris suum reveal a high-conductance, voltage- sensitive Ca(2+) -dependent Cl(-) channel. The hypodermal channel has a conductance of 195 pS in symmetrical 160 mM NaCl. The open probability of the channel is highly voltage-sensitive, and channel activity is not observed when Ca(2+) is reduced to <100 microM.

A systematic examination of the in vitro Ussing chamber and the in situ single-pass perfusion model systems in rat ileum permeation of model solutes.

In situ and in vitro intestinal absorption in the rat ileum was systematically studied and mechanistically quantified in terms of permeability coefficients (P) of a series of [(3)H]steroids as model transcellular permeants, [(3)H]taurocholate utilizing the active membrane transport systems to define the aqueous boundary layer (ABL), and [(14)C]urea and [(14)C]mannitol as pore-hindered paracellular diffusants. In situ single-pass perfusion experiments were performed in isolated ileal segments and blood samples were collected from the cannulated mesenteric vein. For the in vitro experiments, an excised, serosal and muscular layer-removed, ileal tissue was mounted in the Ussing chamber diffusion cells.