Binding site for basic drugs on α<sub>1</sub>‐acid glycoprotein as revealed by chemometric analysis of biochromatographic data

Kaliszan, Roman; Nasal, Antoni; Turowski, Maciej

doi:10.1002/bmc.1130090504

Cited by 63 publications

(39 citation statements)

References 15 publications

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“…One possible explanation for the discrepancy between our results and those of Kaliszan et al (1995) might arise from their use of whole AGP, whereas our method selectively probed the F1*S variant. Perhaps the compounds used by Kaliszan et al (1995) bound preferentially to the A variant, which might differ from F1*S in the effects of drug protonation on affinity.…”

Section: Downloaded Fromcontrasting

confidence: 90%

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Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Taheri

Cogswell²,

Gent³

et al. 2003

J Pharmacol Exp Ther

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Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human ␣ 1 -acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S variant-selective probe previously developed in our laboratory. Equilibriumcompetitive displacement of this probe by LAs, observed by the recovery of AGP's fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (K D ϭ 4.0 Ϯ 0.6 M and Ͼ32 M, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.Understanding the interaction of local anesthetics with plasma proteins is essential to predicting their systemic pharmacology and toxicology. Many basic drugs, including local anesthetics (LAs) and class I antiarrythmics, are bound in blood principally or in part by AGP (Routledge, 1986;Stanski and Watkins, 1986;Wood, 1986;Kremer et al., 1988). The binding of a drug to a plasma protein reduces its free fraction in serum, thus reducing its availability for active uptake or diffusion into surrounding tissue and significantly influencing its pharmacokinetics, toxicity, etc. (Wood, 1986).For example, the local anesthetic bupivacaine binds tightly to AGP (with K D ϭ 1 M) (Essassi et al., 1989), and this binding may mitigate the systemic toxicity of bupivacaine (Wulf et al., 1991;Mazoit et al., 1996).Indeed, altered pharmacokinetics have been observed following the binding of AGP to the LAs lidocaine and cocaine, and the same holds true with other clinically relevant amphipathic amines: amitriptyline, chlorpromazine, nicardipine, and verapamil (Benet and Hoener, 2002). For example, AGP concentration has been shown to correlate inversely with the free fraction of the LA ropivacaine 60 min after epidural injection (Porter et al., 2001). Also, one of the AGP variants...

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Section: Downloaded Fromcontrasting

confidence: 90%

“…This finding is significant in that it contradicts the predictions of the current model of the AGP binding site for amphipathic amines, namely, a region of negative charge near the bottom of a hydrophobic pocket (Kaliszan et al, 1995). Kaliszan at al.…”

Section: Downloaded Frommentioning

confidence: 57%

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Taheri

Cogswell²,

Gent³

et al. 2003

J Pharmacol Exp Ther

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“…The AGP binding and IAM MB binding showed a significant correlation, so it was not possible to use both as independent variables in the regression equations. AGP binds also the positively charged compounds, however, there is a different steric hindrance for molecules that have bulky substitutions near the positive charge [62]. Although AGP can be found in human plasma at low concentrations (approximately 1.5 %) it may be significant in clinical investigations as its concentration depends on the disease state and can increase significantly [63].…”

Section: Resultsmentioning

confidence: 99%

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Valkó¹,

Teague²,

Pidgeon³

2017

ADMET DMPK

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“…The column was maintained at ambient temperature and the compounds were eluted at a flow rate of 1.0 ml/min. Acetonitrile: 100 mM pH 7.0 phosphate buffer (20:80) was used as mobile phase (Kaliszan et al, 1995). The injection volume was 20 µl and the column effluent was monitored at 222 nm.…”

Section: Methodsmentioning

confidence: 99%

Effect of permeation enhancers on the iontophoretic transport of metoprolol tartrate and the drug retention in skin

Nair¹,

Vyas²,

Shah³

et al. 2010

Drug Delivery

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Binding site for basic drugs on α₁‐acid glycoprotein as revealed by chemometric analysis of biochromatographic data

Cited by 63 publications

References 15 publications

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Effect of permeation enhancers on the iontophoretic transport of metoprolol tartrate and the drug retention in skin

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Binding site for basic drugs on α1‐acid glycoprotein as revealed by chemometric analysis of biochromatographic data

Cited by 63 publications

References 15 publications

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

Effect of permeation enhancers on the iontophoretic transport of metoprolol tartrate and the drug retention in skin

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Product

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Binding site for basic drugs on α₁‐acid glycoprotein as revealed by chemometric analysis of biochromatographic data

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein