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Publications (9)24.64 Total impact

  • Philip S Burton, Jay T Goodwin
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    ABSTRACT: Solubility and cellular permeability are two of the most important biopharmaceutical properties impacting the successful development of drug substances. Given the importance of these properties, most pharmaceutical companies have invested in medium to high throughput technologies for early evaluation of these characteristics in the drug discovery funnel in order to select, prioritize or eliminate compounds with unfavorable solubility and/or permeability. However, these technologies require physical samples of the substances to be tested. In order to facilitate the early stages of drug discovery, such as defining compound collection composition, designing combinatorial libraries, and in hit expansion or lead optimization, models for predicting aqueous solubility and permeability in the absence of physical sample are increasingly being employed. In this overview, we will discuss solubility and permeability experimental and computational methods separately and then interrelate them in physiologically relevant models for predicting in vivo performance.
    Combinatorial chemistry & high throughput screening 02/2010; 13(2):101-11. · 2.46 Impact Factor
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    ABSTRACT: Design of successful drug development candidates requires balancing a number of different characteristics simultaneously including intrinsic activity, biopharmaceutical properties, synthesis, stability, and many others. Independently, each of these can be considered a barrier to drug performance or development success (Kerns and Di, 2003). Among the most important of these processes determining in vivo performance are absorption, distribution, metabolism and excretion, collectively referred to as ADME. The structure and physicochemical characteristics of the drug are important determinants of these processes, as are the characteristics of the physiological mechanisms. Further complicating the issue is the interrelationship of many of these processes, frequently in antagonistic ways. Increasing solute lipophilicity, for example, can decrease aqueous solubility, which frequently compromises oral absorption. Also, it can increase metabolic clearance, thus making difficult sustaining the pharmacologically relevant systemic exposure. In contrast, permeability, in many cases, increases with increasing lipophilicity, favoring absorption (Conradi et al., 1996; Hansch et al., 2004). The actual result will be determined by the relative contributions of these two competing phenomena.
    12/2007: pages 195-219;
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    ABSTRACT: The relationship of rotatable bond count (N(rot)) and polar surface area (PSA) with oral bioavailability in rats was examined for 434 Pharmacia compounds and compared with an earlier report from Veber et al. (J. Med. Chem. 2002, 45, 2615). N(rot) and PSA were calculated with QikProp or Cerius2. The resulting correlations depended on the calculation method and the therapeutic class within the data superset. These results underscore that such generalizations must be used with caution.
    Journal of Medicinal Chemistry 11/2004; 47(24):6104-7. · 5.61 Impact Factor
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    ABSTRACT: Significant recent work has focused on predicting drug absorption from structure. Several misperceptions regarding the nature of absorption seem to be common. Among these is that intestinal absorption, permeability, fraction absorbed, and, in some cases, even bioavailability, are equivalent properties and can be used interchangeably. A second common misperception is that absorption, permeability, etc. are discrete, fundamental properties of the molecule and can be predicted solely from some structural representation of the drug. In reality, drug absorption is a complex process dependent upon drug properties such as solubility and permeability, formulation factors, and physiological variables, including regional permeability differences, pH, lumenal and mucosal enzymology, and intestinal motility, among others. This article will explore the influence of these different variables on drug absorption and the implications with regards to attempting to develop predictive drug absorption algorithms.
    Journal of Pharmacology and Experimental Therapeutics 01/2003; 303(3):889-95. · 3.89 Impact Factor
  • J T Goodwin, R A Conradi, N F Ho, P S Burton
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    ABSTRACT: The relationship of solute structure with cellular permeability was probed. Two series of dipeptide mimetics consisting of glycine, alanine, valine, leucine, phenylalanine, and cyclohexylalanine with amino acids in the D-configuration were prepared. Partition coefficients for the peptidemimetics were obtained in the octanol/water (log P(octanol/water)), hydrocarbon/octanol (Delta log P), and heptane/ethylene glycol (log P(heptane/glycol)) systems in order to explore the contributions of solute volume, or surface area, and hydrogen-bond potential to the permeability of the solutes. Permeability coefficients were obtained in Caco-2 cell monolayers as a model of the human intestinal mucosa. The results were interpreted in terms of a partition/diffusion model for solute transport where membrane partitioning into the permeability-limiting membrane microdomain is estimated from the solvent partition coefficients. Neither log P(octanol/water) nor Delta log P alone correlated with cellular permeability for all the solutes. In contrast, log P(heptane/glycol) gave a qualitatively better correlation. With regard to solute properties, log P(octanol/water) is predominantly a measure of solute volume, or surface area, and hydrogen-bond acceptor potential, while Delta log P is principally a measure of hydrogen-bond donor strength. Log P(heptane/glycol) contains contributions from all these solute properties. The results demonstrate that both hydrogen-bond potential and volume of the solutes contribute to permeability and suggests that the nature of the permeability-limiting microenvironment within the cell depends on the properties of a specific solute. Collectively, these findings support the conclusion that a general model of permeability will require consideration of a number of different solute structural properties.
    Journal of Medicinal Chemistry 11/2001; 44(22):3721-9. · 5.61 Impact Factor
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    ABSTRACT: Efficient transport of intact drug (solute) across the intestinal epithelium is typically a requirement for good oral activity. In general, the membrane permeability of a solute is a complex function of its size, lipophilicity, hydrogen bond potential, charge, and conformation. In conjunction with theoretical/computational and in vitro drug transport studies, seven dipeptide (R(1)-D-Xaa-D-Phe-NHMe) homologues were each dissolved in a micellar d(38)-dodecylphosphocholine solvent system. In this homologous dipeptide series, factors such as size, lipophilicity, hydrogen-bond potential, and charge were either tightly controlled or well-characterized by other methods in order to investigate by nmr how conformational factors relate to transport. Nuclear Overhauser effect spectroscopy experiments and amide-NH-H(2)O chemical exchange rates showed that the five more lipophilic dipeptides were predominately associated with micelle, whereas the two less lipophilic analogues were not. Rotating frame nuclear Overhauser effect spectroscopy derived interproton distance restraints for each analogue, along with (3)J(HH)-derived dihedral restraints, were used in molecular dynamics/simulated annealing computations. Our results suggest that-other factors being equal-flexible dipeptides having a propensity to fold together nonpolar N- and C-terminal moieties allow greater segregation of polar and nonpolar domains and may possess enhanced transport characteristics. Dipeptides that were less flexible or that retained a less amphiphilic conformation did not have comparably enhanced transport characteristics. We suggest that these conformational/transport correlations may hold true for small, highly functionalized solutes (drugs) in general.
    Biopolymers 05/2000; 53(5):396-410. · 2.88 Impact Factor
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    ABSTRACT: Efficient transport of intact drug (solute) across the intestinal epithelium is typically a requirement for good oral activity. In general, the membrane permeability of a solute is a complex function of its size, lipophilicity, hydrogen bond potential, charge, and conformation. In conjunction with theoretical/computational and in vitro drug transport studies, seven dipeptide (R1–D-Xaa–D-Phe–NHMe) homologues were each dissolved in a micellar d38-dodecylphosphocholine solvent system. In this homologous dipeptide series, factors such as size, lipophilicity, hydrogen-bond potential, and charge were either tightly controlled or well-characterized by other methods in order to investigate by nmr how conformational factors relate to transport. Nuclear Overhauser effect spectroscopy experiments and amide-NH–H2O chemical exchange rates showed that the five more lipophilic dipeptides were predominately associated with micelle, whereas the two less lipophilic analogues were not. Rotating frame nuclear Overhauser effect spectroscopy derived interproton distance restraints for each analogue, along with 3JHH-derived dihedral restraints, were used in molecular dynamics/simulated annealing computations. Our results suggest that—other factors being equal—flexible dipeptides having a propensity to fold together nonpolar N- and C-terminal moieties allow greater segregation of polar and nonpolar domains and may possess enhanced transport characteristics. Dipeptides that were less flexible or that retained a less amphiphilic conformation did not have comparably enhanced transport characteristics. We suggest that these conformational/transport correlations may hold true for small, highly functionalized solutes (drugs) in general. © 2000 John Wiley & Sons, Inc. Biopoly 53: 396–410, 2000
    Biopolymers 03/2000; 53(5):396 - 410. · 2.88 Impact Factor
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    ABSTRACT: The therapeutic efficacy of an orally administered drug is dictated not only by its pharmacological properties such as potency and selectivity, but also its pharmacokinetic properties such as its access to the site of activity. Thorough evaluation of the physicochemical and biological barriers to drug delivery is essential to the selection and successful development of drug candidates. We have demonstrated previously that cellular permeability, as a primary component of drug delivery, is principally dependent upon the desolvation potential of the polar functionalities in the molecule and, secondarily, upon the solute lipophilicity [Conradi, R.A., Hilgers, A.R., Ho, N.F.H., Burton, P.S. (1992). The influence of peptide structure on transport across Caco-2 cells. II. Peptide bond modification which results in improved permeability. Pharm. Res. 9, 473-479]. Increasingly sophisticated computational methods are becoming available for describing molecular structural features proposed to correlate with such molecular physicochemical determinants of permeability. Herein we examine the relationships of various computationally derived molecular geometric descriptors for a set of peptides and peptidomimetics, in the context of experimentally measured hydrogen-bond potentials and lipophilicities, with their cellular permeabilities. These descriptors include molecular volume, polar and non-polar surface areas and projected molecular cross-sectional areas. Particular attention is paid to the roles of solvation treatments and other computational factors in descriptor generation, deconvolution of cellular transport mechanisms and statistical analyses of the resulting data for the development of valid, structure-based and mechanistically meaningful models of cellular permeability. No significant correlation of cellular permeability with computed descriptors was found. This was primarily because of our inability to identify surrogates for hydrogen-bond desolvation potential for the solutes from among these descriptors.
    European Journal of Allergy and Clinical Immunology 05/1999; 53(4):355-69. · 1.30 Impact Factor
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    ABSTRACT: Cellular efflux pathways function to remove both endogenous and exogenous substances from the cell. In the case of a polarized cellular barrier, such as the epithelium, these pathways serve an excretory or secretory role in transporting solutes out of tissue. Although well recognized in organs typically associated with drug excretion such as liver and kidney, similar transport pathways have been found in other tissues including the intestinal mucosa and the endothelial cells comprising the blood-brain barrier. Current evidence suggests that these systems may act as barriers to drug absorption into the tissues in which they are found. More recent studies have shown that hydrophobic peptides such as cyclosporin A are substrates for polarized efflux. In this review we examine the evidence for these mechanisms as absorption barriers and the use of in vitro transport models for characterizing this phenomenon. The presence of such pathways may help explain the poor membrane permeability of peptides which, along with metabolism, contributes to their poor in vivo performance.
    Advanced Drug Delivery Reviews. 01/1997;