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Drosophila pseudoobscura harbors a rich polymorphism for paracentric inversions on the third chromosome, and the clines in the inversion frequencies across the southwestern United States indicate that strong natural selection operates on them. Isogenic inversion strains were made from isofemale lines collected from four localities, and eight molecular(More)
While each of the two key parameters of oral drug absorption, the solubility and the permeability, has been comprehensively studied separately, the relationship and interplay between the two have been largely ignored. For instance, when formulating a low-solubility drug using various solubilization techniques: what are we doing to the apparent permeability(More)
The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has(More)
A quasi-equilibrium mass transport analysis has been developed to quantitatively explain the solubility-permeability interplay that exists when using cyclodextrins as pharmaceutical solubilizers. The model considers the effects of cyclodextrins on the membrane permeability (P(m)) as well as the unstirred water layer (UWL) permeability (P(aq)), to predict(More)
Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability(More)
The purpose of this paper was to study the solubility-permeability interplay in formulation development for oral administration of poor aqueous solubility drugs. The apparent solubility of the lipophilic drug carbamazepine was measured in systems containing various levels of the co-solvent PEG-400. The corresponding permeability was then measured in the(More)
Physiologically based pharmacokinetic (PBPK) modeling tools have become an integral part of the modern drug discovery-development process. However, accurate PK prediction of enabling formulations of poorly soluble compounds by applying PBPK modeling has been very limited. This is because current PBPK models rely only on thermodynamic drug solubility inputs(More)
Although the extraordinary solubility advantage afforded by cyclodextrins has led to their widespread use as pharmaceutical solubilizers, several reports have emerged that cyclodextrins may also reduce the apparent permeability of the drug. With the purpose to investigate this solubility-permeability interplay, we have recently developed a mathematical mass(More)
The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F(abs)) in humans is 90% or higher. This direct correlation between human permeability and F(abs) has been recently controversial, since the β-blocker sotalol showed high F(abs) (90%) and low Caco-2 permeability. The purpose of this study was to investigate the(More)
We have recently reported the interplay between apparent aqueous solubility and intestinal membrane permeability, showing the trade-off between the two when using cyclodextrin- and surfactant-based systems as solubility-enabling formulations. In these cases, the decreased permeability could be attributed directly to decreased free fraction of drug due to(More)