pK<sub>a</sub> Values of Medicinal Compounds in Pharmacy Practice

Newton, David W.; Kluza, Ronald B.

doi:10.1177/106002807801200906

Cited by 180 publications

(78 citation statements)

References 68 publications

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“…Accumulation of chloroquine in lysosomes "several hundred-fold" has been observed (De Duve et al 1974). Quinacrine, another bivalent base accumulating in lysosomes (Duvvuri et al 2004) has a log K OW of 4.79 and pK a -values at 10.2 and 8.2 (Hansch et al 1995, Newton andKluza 1978). The properties of both compounds are in the predicted optimum range.…”

Section: Bivalent Bases (Z = +2)mentioning

confidence: 99%

“…Significantly, the anti-malaria agent and lysosome-targeting drug par excellence (De Duve 1974) chloroquine is a bivalent base with pK a1 at 9.94, pK a2 at 8.10 (Newton and Kluza 1978). The log K OW of chloroquine is 4.38 (Hansch et al 1995).…”

Section: Bivalent Bases (Z = +2)mentioning

confidence: 99%

“…LTR is a monovalent base with log K OW at 2.1 and pK a of 7.5 (Duvvuri et al 2004). QNC is a bivalent base with log K OW at 4.69 and pK a -values at 10.47 and 7.12 (ACD 2007), 10.2 and 8.2 (Newton and Kluza 1978) or 10.39 und 7.72 (Rosenberg and Schulman 1978). Both LTR and QNC accumulate in lysosomes.…”

Section: Quantitative Measurements Of Concentration In Lysosomesmentioning

confidence: 99%

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Quantitative modeling of selective lysosomal targeting for drug design

et al. 2008

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Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick-Nernst-Planck-equation. The cell model considers the diffusion of neutral and ionic molecules across biomembranes, dissociation to mono-or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono-and bivalent bases with intermediate to high log Kow. These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation. This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions.

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Section: Bivalent Bases (Z = +2)mentioning

confidence: 99%

Section: Bivalent Bases (Z = +2)mentioning

confidence: 99%

Section: Quantitative Measurements Of Concentration In Lysosomesmentioning

confidence: 99%

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Quantitative modeling of selective lysosomal targeting for drug design

et al. 2008

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“…2. Hydroxyzine carries two tertiary amino groups with pK a,1 ‫ס‬ 7.2 and pK a,2 ‫ס‬ 2.1 (Newton & Kluza, 1978). The surface area, A S , is large at low pH due to charge repulsion effects and decreases with increasing pH in a sigmoidal manner.…”

Section: The Cross-sectional Area Of Drugsmentioning

confidence: 99%

Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

Fischer

Gottschlich

Seelig

1998

Journal of Membrane Biology

340

302

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Abstract. 53 compounds with clinically established ability to cross or not to cross the blood-brain barrier by passive diffusion were characterized by means of surface activity measurements in terms of three parameters, i.e., the air-water partition coefficient, K aw , the critical micelle concentration, CMC D , and the cross-sectional area, A D . A three-dimensional plot in which the surface area, A D , is plotted as a function of K −1 aw and CMC D shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, A D > 80 Å 2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, A D ≅ 50 Å 2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (A D < 50 Å 2 ) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, K lw , measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, bi ‫ס‬ 34 ± 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, A D , according to K lw ‫ס‬ const. K aw exp(−A D bi /kT) where kT is the thermal energy. The cross-sectional area of the molecule oriented at a hydrophilic-hydrophobic interface is thus the main determinant for membrane permeation provided the molecule is surface active and has a pK a > 4 for acids and a pK a < 10 for bases.

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“…Sulfonylureas ( Fig. 1) are weak acids, with pK a values of 5.43 (tolbutamide) and 5.3 (glibenclamide) in aqueous solution (17). The pK a of the sulfonamide group by itself is 10.1 in solution but is lowered to between 5 and 6.5 when the group is next to a carbonyl.…”

Section: Resultsmentioning

confidence: 99%

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

et al. 2003

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Because sulfonylureas directly activate the exocytotic machinery, we were interested in the extent to which these compounds penetrate the ␤-cell plasma membrane and the underlying molecular mechanism(s). We now provide evidence that sulfonylureas cross phospholipid bilayer membranes rapidly and effectively by a free-diffusion mechanism. Two sulfonylurea compounds investigated by 1 H nuclear magnetic resonance spectroscopy, glibenclamide and tolbutamide, were found to incorporate into phospholipid bilayers, with the ionizable sulfonamide exposed to the aqueous interface and its apparent dissociation constant (pK a ) increased to ϳ7.0. Diffusion of weak amphiphilic acids across membranes is associated with a measurable change in pH. Thus, by using a fluorescencebased pH assay, we could investigate the diffusion of sulfonylurea compounds across phospholipid bilayer membranes. A fluorescent pH indicator (pyranin or [2,7-bis (2-carboxyethyl)-5(6)-carboxyfluorescein] [BCECF]) was trapped in egg phosphatidylcholine vesicles. Addition of glibenclamide decreased internal pH (pH in ), and addition of albumin reversed this drop by 50%. With the same amount of tolbutamide, the decrease in pH in was much smaller, primarily because of the lower partitioning of tolbutamide into phospholipid bilayers. Using similar protocols, we also demonstrated diffusion by the same mechanism across the ␤-cell plasma membrane. Thus, we now provide a molecular mechanism by which sulfonylureas can penetrate the plasma membrane and reach intracellular sites regulating exocytosis. Diabetes 52:2526 -2531, 2003 S ulfonylureas are drugs that stimulate secretion of insulin from the pancreatic ␤-cells (1,2) and are therefore used extensively in the treatment of type 2 diabetes. It is well established that sulfonylureas stimulate insulin release by interacting with the high-affinity 140-kDa SUR1 protein of the ATP-regulated K ϩ channel at the cytoplasmic leaflet of the plasma membrane. This interaction closes the channel, causing membrane depolarization, the opening of voltage-gated L-type Ca 2ϩ channels, an increase in cytoplasmic-free Ca 2ϩ concentration, and the activation of the secretory machinery (3,4). We have also shown that sulfonylureas stimulate insulin exocytosis by directly interacting with the secretory machinery and not through closure of the plasma membrane ATP-regulated K ϩ channel (5-7). This effect may constitute part of the therapeutic benefits of sulfonylureas and contribute to their hypoglycemic action in diabetes. Although this direct effect of sulfonylureas on insulin exocytosis is now well established and suggestions for underlying molecular mechanisms have been put forward (8), the physiological relevance of these findings are still in question. This skepticism originates primarily from the difficulty in envisaging how the sulfonylureas bypass the ␤-cell plasma membrane rapidly and effectively, thereby interacting with intracellular binding sites involved in the regulation of exocytosis. Indeed, earlier studies suggested that ...

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pK_a Values of Medicinal Compounds in Pharmacy Practice

Cited by 180 publications

References 68 publications

Quantitative modeling of selective lysosomal targeting for drug design

Quantitative modeling of selective lysosomal targeting for drug design

Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

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pKa Values of Medicinal Compounds in Pharmacy Practice

Cited by 180 publications

References 68 publications

Quantitative modeling of selective lysosomal targeting for drug design

Quantitative modeling of selective lysosomal targeting for drug design

Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

Sulfonylureas Rapidly Cross Phospholipid Bilayer Membranes by a Free-Diffusion Mechanism

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pK_a Values of Medicinal Compounds in Pharmacy Practice