Potentiometric determination of dissociation constants

Benet, Leslie Z.; Goyan, Jere E.

doi:10.1002/jps.2600560602

Cited by 112 publications

(41 citation statements)

References 68 publications

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“…Although pK a values determined by 13 C NMR chemical shifts in (CD 3 ) 2 SO may differ markedly from those determined in water, pK a values of aryl and pyrrolic carboxylic acids derived by NMR in aqueous solutions containing up to 31 mol % (CD 3 ) 2 SO differ little from values determined in the absence of the organic cosolvent (28). Thus, the caveat that pK a values measured in aqueous organic solvents cannot be extrapolated to give reliable pK a values for water (46) does not apply to the present 13 C NMR method when aqueous dimethyl sulfoxide solutions containing excess water are used.…”

mentioning

confidence: 72%

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Lightner

Holmes

McDonagh

1996

Journal of Biological Chemistry

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Biliverdin and bilirubin are naturally-occurring tetrapyrrolic bile pigments containing two propionic acid side chains. These side chains, and their propensity for ionization, are critical in the biological disposition of the pigments. Surprisingly, accurate dissociation constants for the propionic acid groups of biliverdin are unknown, and a wide range of values, extending over some 4 orders of magnitude, has been suggested for the K a values of the propionic acid groups of bilirubin in aqueous solutions. Recently, pK a values of 6.7-9.3 have been reported for bilirubin-values much greater than the value of ϳ5 typical of propionic acid groups. These curiously high values, currently being used to explain the biological transport and metabolism of bilirubin and related compounds, have been attributed to intramolecular hydrogen bonding. We have determined the pK a values of 99% Bilirubin and biliverdin are blue-green and yellow-orange pigments formed from heme during normal metabolism in humans and other animals (1, 2). Like heme, biliverdin and bilirubin have two propionic acid groups and low solubility in water (1-3). The acidity constants of bilirubin have been determined many times during the past 40 years (4 -13), but those of heme and biliverdin have not been measured (3). A mean pK a of ϳ5.3 has been predicted for porphyrin dicarboxylic acids (14), and pK a values of ϳ5.0 and ϳ7.2 have been estimated for biliverdin (3). A wide range of pK a values has been reported for bilirubin, with most investigators favoring a pK a of 6.2 to 6.5 (15), but recent determinations suggest that the true pK a values are even higher (6.8 to Ն 9.3) because of intramolecular hydrogen bonding (11,12). Since most carboxylic acid pK a values are ϳ5 and values Ͼ6 are seldom encountered (16 -18), these recent determinations imply a remarkable and unprecedented effect of intramolecular hydrogen bonding on proton dissociation. To investigate this effect, we have used 13 C NMR to study the dissociation of hydrogen-bonded and non-hydrogen-bonded pyrrolic acids and to determine the pK a values of mesobilirubin-XIII␣ (1) and mesobiliverdin-XIII␣ (2), two synthetic surrogates that differ from bilirubin and biliverdin, respectively, only by trivial differences in the nature, i.e. vinyl groups reduced to ethyl, and sequence of alkyl side chains on the lactam rings. Being remote from the propionic acid side chains, the alkyl substituents on the lactam rings are expected

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confidence: 72%

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Lightner

Holmes

McDonagh

1996

Journal of Biological Chemistry

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“…MVC and CMPD167 were slightly less active against virus replication in macaque than human PBMC, with CMPD167 being the marginally more potent inhibitor (Table 1). 3 H-MVC binding assays yielded mean equilibrium dissociation constant (K D ) values of 1.36 and 0.86 nM for macaque and human CCR5, respectively, although the inhibitor dissociated ϳ10-fold more quickly from macaque CCR5 (30). The IC 50 s for MVC inhibition of chemokine binding to macaque and human CCR5 were 17.5 and 7.2 nM (30); for CMPD167 they are 7.5 and 4.5 nM (M. Springer, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Malcolm

Veazey

Geer

et al. 2012

Antimicrob Agents Chemother

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e Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 g/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ϳ10 6 -fold greater than the 50% inhibitory concentrations (IC 50 s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

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“…Sufficient time interval between stirring and potential measurement during the titration allowed to assure the protonation/deprotonation equilibrium in H,O/EtOH. Titration curves were recorded using a Metrohm titroprocessor model 670 (Herisau, Switzerland) and pK, values calculated using a non-logarithmic linearisation of the titration curve to overcome the problem of dilution during titration [28] [29].…”

Section: Methodsmentioning

confidence: 99%

Physicochemical and Structural Properties of Non‐Steroidal Anti‐inflammatory Oxicams

Tsai

Carrupt

Tayar

et al. 1993

Helvetica Chimica Acta

105

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Using the five therapeutic oxicams 1-5, we showed that isosteric replacements result in remarkable changes in the physicochemical and structural properties of congeners. Thus, the acidity of the phenolic OH group is relatively higher in the oxicams containing a pyridinyl moiety, i.e. in piroxicam (l), tenoxicam (2), and lornoxicam (3), due to their zwitterionic nature. This consequently influences their lipophilicity profile at different ionization states. Furthermore, partitioning behaviour in octan-1 -ol/H,O and heptane/H,O systems suggests an internal H-bond between the enolic OH and the amide C=O group. The anionic oxicams readily partition into the octanol phase at pH 7.4 and not at all into the heptane phase. Only the partition coefficients of oxicams measured in the heptane/H20 system, but not in the octanol/H20 system, correlate with their transfer across the blood-brain barrier. This implies that only the neutral form of oxicams crosses the blood-brain barrier.

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Potentiometric determination of dissociation constants

Cited by 112 publications

References 68 publications

On the Acid Dissociation Constants of Bilirubin and Biliverdin

On the Acid Dissociation Constants of Bilirubin and Biliverdin

Sustained Release of the CCR5 Inhibitors CMPD167 and Maraviroc from Vaginal Rings in Rhesus Macaques

Physicochemical and Structural Properties of Non‐Steroidal Anti‐inflammatory Oxicams

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