The spectrophotometric determination of the dissociation constants of theophylline, theobromine, and caffeine

Turner, Arthur; Osol, Arthur

doi:10.1002/jps.3030380312

Cited by 13 publications

(5 citation statements)

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“…The next step was to find out whether internal application of caffeine would also influence the behaviour of the Na efflux in the same way as external application of caffeine. This was a matter of some importance since caffeine is known to decrease Ca2+ uptake as well as increase its release by the sarcoplasmic reticulum (Weber, 1968;Weber & Herz, 1968) and to exist as a free base over a wide pH range (Turner & Osol, 1949). The results obtained with microinjection of 100 mm caffeine at pH 7-4 showed a 21.4 +2.9 % rise in the Na efflux (n = 10) and that the stimulation was never preceded by inhibition.…”

Section: Resultsmentioning

confidence: 98%

The effects of caffeine on sodium transport, membrane potential, mechanical tension and ultrastructure in barnacle muscle fibres

Bittar¹,

Hift²,

Huddart³

et al. 1974

The Journal of Physiology

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SUMMARY1. The effects of graded concentrations of caffeine on the Na efflux were investigated. External application of 10 mm caffeine usually caused a biphasic response, viz, a fall, followed by a rise in the Na efflux. 1 and 5 mm caffeine usually caused stimulation. Only the stimulator phase of this response depended on the presence of external Ca2+.2. Internal application of 100 mm~caffeine caused a small rise in the Na efflux, the magnitude of which was independent of external Ca2+ and comparable to that obtained with external application of 1 mm caffeine. This action, however, could be greatly augmented by pre-treating the fibre with x 10-5 M ouabain.3. The rise in Na efflux caused by external application of 10 mmc affeine could be greatly augmented by pre-treating the fibre with 5 x IO--M ouabain. The observed stimulatory response was biphasic, more so in the absence of external Ca2+. Restoration of external Ca2+ following the onset of the second stimulatory phase resulted in further rise of the Na efflux. Measurements of the Na efflux during treatment with graded concentrations of ouabain and 10 mm~caffeine showed that the rate coefficient for Na efflux varied with the ouabain concentration in the range 10-8_10-4 M. Measurements of the ouabain-insensitive Na efflux before and during treatment with 10 mmw caffeine in bathing media containing varying concentrations of Ca, disclosed the existence of two Ca2+_ thresholds, one in the 0-2-5 mm range and the other in the 12-5-15 mm range.4. Comparisons were made between the effects on the Na efflux of * Permanent address: Department of Biological Sciences, University-of Lancaster, Bailrigg, Lancaster LAI 4YQ, England.1-2 2~~E. EDWARD BITTAR AND OTHERS 10 mm caffeine followed by external acidification, and external acidification, followed by 10 mm caffeine. The magnitude of the response of the ouabaininsensitive Na efflux to external acidification before treatment with 10 mm caffeine was greater than that found when external acidification followed external application of the alkaloid. It also was considerably greater than that of the response to external application of 10 mm caffeine before external acidification.5. External application of 10 mm procaine prevented 10 mmw caffeine from stimulating the Na efflux, and from inducing contractures. Internal application of 100 mm-EGTA reduced the response of the Na efflux to 10 mmw caffeine, and also prevented the fibre from contracting. External application of 10-4m diphenylhydantoin reduced the response of the Na efflux to 10 mmw caffeine but failed to prevent the development of contractures.6. Internal application of 0-05 m-cGMP, cAMP or its dibutyryl derivative caused a large rise in the Na efflux. The magnitude of the effects observed in ouabain-poisoned fibres was often greater than that in unpoisoned fibres. Internal application of 2-5 units/ml. phosphodiesterase beforehand failed to reduce the magnitude of the stimulatory response to injected cyclic nucleotides. Injected phosphodiesterase also failed to reduce th...

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Section: Resultsmentioning

confidence: 98%

The effects of caffeine on sodium transport, membrane potential, mechanical tension and ultrastructure in barnacle muscle fibres

Bittar¹,

Hift²,

Huddart³

et al. 1974

The Journal of Physiology

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“…Similar to L-tryptophan, there also exists multiple weak non-specific caffeine binding sites on HSA282930. Titration experiments were again conducted with varying mixing times (0.15 seconds to 2.0 seconds) and varying protein concentrations (25 μM, 50 μM and 100 μM).…”

Section: Resultsmentioning

confidence: 99%

“…To explore this notion further, we selected caffeine as an alternative, weaker binding ligand with a reported K D value for binding to HSA varying between 0.9 mM and 1.5 mM 21 28 29 30 . Similar to L-tryptophan, there also exists multiple weak non-specific caffeine binding sites on HSA 28 29 30 . Titration experiments were again conducted with varying mixing times (0.15 seconds to 2.0 seconds) and varying protein concentrations (25 μM, 50 μM and 100 μM).…”

Section: Resultsmentioning

confidence: 99%

Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

Huang

Bonnichon

Claridge

et al. 2017

Sci Rep

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“…Theophylline can also accept a proton and ionize as a cation under similar conditions. The ionization 600 HARDMAN 12 In each case, the pK« value for theophylline and caffeine when functioning as proton acceptors (bases) was less than 1.0. This indicates that, when these drugs are placed in a medium the pH of which is greater than 6.5, less than 0.0009 per cent of a given dose of the drugs will exist in the cationic state.…”

Section: Ionization Characteristics Of the Xanthine Drugsmentioning

confidence: 95%

“…The acidic ionization constant for theophylline has been determined by Turner and Osol. 12 They indicate this pK a value to be approximately 8.7. Thus, at pH 7.5 we have approximately 94 per cent of a given dose of theophylline present in the nonionized form while approximately 6 per cent of the drug exists in the anionic form.…”

Section: Ionization Characteristics Of the Xanthine Drugsmentioning

confidence: 98%

Molecular Form of Theophylline Responsible for Positive Inotropic Activity

Hardman

1962

Circulation Research

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• The purpose of this paper is to identify the active molecular species of a drug, theophylline, which exists simultaneously in the ionized and nonionized states at pH 7.4. Previous studies by Hardman et al. 1 and Baird and Hardman 2 have related changes in cardiac function to the concentration of nonionized or ionized drugs in the extracellular fluid perfusing isolated hearts. Such correlations do not establish the active form of the drug but do provide some insight into the probable active form. Waddell and Hardman 3 have recently demonstrated a linear relationship between the pH of the extracellular perfusion fluid (pH e ) and the pH of intracellular water (pH|) in turtle ventricular tissue when pH ( . is varied over a range of 6.5 to 9.5. This information may be utilized to identify the active molecular species of ionizable drugs since intracellular, as well as extracellular, concentrations of the ionized and nonionized drug forms in their respective aqueous phases can be estimated simultaneously and correlated with the pharmacological activity of the drug under investigation. Methods DOG HEART-LUNG PREPARATIONA modification of the Krayer-Mendez 4 denervated henrt-lun

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The spectrophotometric determination of the dissociation constants of theophylline, theobromine, and caffeine

Cited by 13 publications

References 2 publications

The effects of caffeine on sodium transport, membrane potential, mechanical tension and ultrastructure in barnacle muscle fibres

The effects of caffeine on sodium transport, membrane potential, mechanical tension and ultrastructure in barnacle muscle fibres

Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

Molecular Form of Theophylline Responsible for Positive Inotropic Activity

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