On the modulating effects of temperature, albumin, pH and calcium on the free fractions of phenobarbitone and phenytoin

Melten, Joost W.; Wittebrood, A.; Wemer, J.; Faber, D.B.

doi:10.1111/j.2042-7158.1986.tb03102.x

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…Despite its limited statistical significance, eq 3 predicts %B(DAB) reasonably well for pregnenolone (85%, log D 7.4 = 4.22) and testosterone (76%, log D 7.4 = 3.13) taking values reported by Fischer et al (80 and 60%, respectively); the same may also be said for phenytoin (log D 7.4 = 2.47; 81% is the experimental value reported in ref ; 71% is the calculated result). Equation 3 also predicts a value of about 37% for imipramine (log D 7.4 = 3.0), in excellent agreement with the 35% reported in the literature .…”

Section: Resultssupporting

confidence: 63%

Contribution of Ionization and Lipophilicity to Drug Binding to Albumin: A Preliminary Step toward Biodistribution Prediction

Ermondi

Lorenti

2004

J. Med. Chem.

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Understanding the molecular mechanisms governing albumin binding is a major challenge in absorption-distribution-metabolism-excretion prediction. To gain insight into this complex field, an ultracentrifugation method to measure the drug fraction bound to bovine serum albumin [%B(DAB)] is presented. The second part of the study shows the dependence of the experimental binding parameter on ionization and lipophilicity descriptors (pK(a) and log D(oct)(7.4) for a series of 14 structurally diverse drugs. Finally, a docking strategy is used to rationalize the findings; the results confirm the mostly nonspecific nature of the interaction of albumin with neutral ligands.

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Section: Resultssupporting

confidence: 63%

Contribution of Ionization and Lipophilicity to Drug Binding to Albumin: A Preliminary Step toward Biodistribution Prediction

Ermondi

Lorenti

2004

J. Med. Chem.

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“…Phenytoin, with two amines, does have a greater polar character. Due to its polar nature, it binds strongly to serum proteins, and this effect increases as pH is increased (Melten et al, 1986), so its effective concentration in the cultures may be reduced through binding to serum proteins in the culture medium.…”

Section: Downloaded Frommentioning

confidence: 99%

2-Aminoethoxydiphenyl Borate Directly Inhibits Channels Composed of Connexin26 and/or Connexin32

Tao

Harris²

2006

Mol Pharmacol

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2-Aminoethoxydiphenyl borate (2-APB), a commonly used blocker of IP 3 -induced calcium ion release and of store-operated channels, inhibits gap junction conductance when applied to cultured cells. The character and pharmacology of this inhibition was explored using 1) hemichannels composed of connexin32 (Cx32) and/or connexin26 (Cx26) purified from native sources and from transfected HeLa cells in which the connexin had a cleavable C-terminal epitope tag and 2) the corresponding junctional channels. Using reconstituted hemichannels in a liposome-based transport-specific fractionation assay (TSF), 2-APB reversibly inhibited homomeric Cx32 and heteromeric Cx26/Cx32 channels from native tissue and their tagged forms from HeLa cells. The IC 50-TSF value of the inhibition was ϳ47M at pH 6.5. 2-APB did not inhibit tagged homomeric Cx26 channels even after tag cleavage (leaving several amino acids at the carboxyl terminus). Protonated 2-APB is the inhibitory agent, but channel sensitivity to 2-APB also increases as pH is lowered. To help define the chemical requirements for inhibition, the effects of four structural analogs of 2-APB were determined. The inhibitory action of 2-APB was shown to be distinct from that of aminosulfonates. 2-APB and its analogs, except phenytoin, inhibited dye-coupling through junctional channels formed by all the tagged channel forms except Cx26, consistent with the TSF studies. However 2-APB significantly inhibited dye coupling between cells expressing untagged Cx26, suggesting that an unmodified C terminus is required for action on Cx26 channels. These results show that protonated 2-APB directly and reversibly inhibits connexin channels composed of Cx26 and/or Cx32 and suggest involvement of the carboxyl-terminal domain.

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“…The plasma Concentration of drugs with very low affinity (Derendorf 1987) or very high affinity (Rosano 1985) for blood cells is affected by the haematocrit value. Both PHT (Sherwin et al 1976;Tamura et al 1987) and CPZ (Bickel The eflert of' concentration qfplasma proteins Lowering the albumin concentration in plasma yields an increase in the unbound (free) fraction of certain drugs (Javaid et al 1985;Shirkey et al 1985;Melten et al 1986). Our results show that the decrease in the PHT and CPZ in plasma with decrease in the total protein concentration may be attributed to an increase in the free fraction of the drug in plasma, which may result in increased drug binding to blood cells.…”

Section: The Eflkct Of'haematocrit Raluementioning

confidence: 65%

The Effects of Haematocrit, Plasma Protein Concentration and Temperature of Drug-containing Blood In-vitro on the Concentrations of the Drug in the Plasma

Tamura

Sugimoto

Sato

et al. 1990

Journal of Pharmacy and Pharmacology

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Factors which influence the plasma drug concentrations in whole blood have been investigated in-vitro using human blood containing radio-labelled phenytoin or chlorpromazine. Phenytoin (3.55 micrograms mL-1, 0.01 mM) or chlorpromazine (2.74 micrograms mL-1, 0.01 mM) was mixed with normal or modified blood and the plasma drug level was measured. Plasma phenytoin and chlorpromazine levels decreased with decrease in the protein concentration of plasma, but were not influenced by addition of gamma-globulin to the blood specimen. Plasma phenytoin levels increased with an increase in haematocrit from 20 to 45%, whereas the chlorpromazine level remained constant. The partition coefficients of phenytoin and chlorpromazine between blood cells and plasma were almost the same at various haematocrit values. By cooling the blood containing each drug to 4 degrees C, plasma phenytoin and chlorpromazine levels were higher compared with those at 37 degrees C. Similar temperature effects on the drug levels in plasma were obtained when the washed erythrocytes were resuspended in albumin medium, but not when resuspended in saline.

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On the modulating effects of temperature, albumin, pH and calcium on the free fractions of phenobarbitone and phenytoin

Cited by 10 publications

References 6 publications

Contribution of Ionization and Lipophilicity to Drug Binding to Albumin: A Preliminary Step toward Biodistribution Prediction

Contribution of Ionization and Lipophilicity to Drug Binding to Albumin: A Preliminary Step toward Biodistribution Prediction

2-Aminoethoxydiphenyl Borate Directly Inhibits Channels Composed of Connexin26 and/or Connexin32

The Effects of Haematocrit, Plasma Protein Concentration and Temperature of Drug-containing Blood In-vitro on the Concentrations of the Drug in the Plasma

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