Familial dysalbuminemic hyperthyroxinemia may result in altered warfarin pharmacokinetics

Petersen, Charles E.; Ha, Chung-Eun; Harohalli, Krishna; Park, David; Bhagavan, N.V.

doi:10.1016/s0009-2797(99)00143-x

Cited by 35 publications

(27 citation statements)

References 23 publications

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“…Direct contact between the benzyl ring and the side chain of Trp-214 explains why modification of this residue reduces warfarin binding to HSA (33). The proximity of the benzyl ring to Arg-218 also accounts for the reduction in binding affinity associated with mutations at this position (6). The coumarin moiety fits into the main chamber furthest from the entrance, which is the same portion of site I that is occupied by TIB (11).…”

Section: Resultsmentioning

confidence: 99%

“…Much of this work has been performed using binding and competition assays to map out the number and selectivity of binding sites on the protein (13, 16 -18, 34), although more recently, mutagenesis techniques have been applied to the study of drug interactions (6,35). Although initial crystallographic studies at moderate resolution have focused mainly on the binding of TIB, a drug analogue, to HSA (10,11), there has been a lack of high resolution structural information with which to interpret the amassed biochemical and biophysical data on HSA-drug interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Although the effects on pharmacokinetics of drug-drug competition for the same sites on HSA are generally held to be of little clinical import (4,5), physiological or diseased states that cause variations in the plasma levels of albumin or its primary endogenous ligands can influence drug binding and may require dosages to be closely monitored. Added to this, genetic polymorphisms in HSA can also alter drug binding and may further complicate the clinical picture (6,7). To understand the molecular basis of these effects, structural information is required to fully delineate the binding sites for drugs and endogenous ligands.…”

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confidence: 99%

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Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Petitpas¹,

Bhattacharya²,

Twine³

et al. 2001

Journal of Biological Chemistry

777

605

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Human serum albumin (HSA) is an abundant transport protein found in plasma that binds a wide variety of drugs in two primary binding sites (I and II) and can have a significant impact on their pharmacokinetics. We have determined the crystal structures at 2.5 Å-resolution of HSA-myristate complexed with the R-(؉) and S-(؊) enantiomers of warfarin, a widely used anticoagulant that binds to the protein with high affinity. The structures confirm that warfarin binds to drug site I (in subdomain IIA) in the presence of fatty acids and reveal the molecular details of the protein-drug interaction. The two enantiomers of warfarin adopt very similar conformations when bound to the protein and make many of the same specific contacts with amino acid side chains at the binding site, thus accounting for the relative lack of stereospecificity of the HSA-warfarin interaction. The conformation of the warfarin binding pocket is significantly altered upon binding of fatty acids, and this can explain the observed enhancement of warfarin binding to HSA at low levels of fatty acid.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Petitpas¹,

Bhattacharya²,

Twine³

et al. 2001

Journal of Biological Chemistry

777

605

View full text Add to dashboard Cite

show abstract

“…4) The knowledge of amino acid residues of potential importance for site I has greatly facilitated detailed studies of ligand binding to the site. For example, high-affinity binding of warfarin has been studied using selected rHSA mutants 13,16) and by X-ray diffraction of rHSA-warfarin-myristate complexes (Fig. 1B).…”

Section: Ligand Bindingmentioning

confidence: 99%

Practical Aspects of the Ligand-Binding and Enzymatic Properties of Human Serum Albumin.

Kragh‐Hansen

Chuang

Otagiri

2002

Biological & Pharmaceutical Bulletin

939

776

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Recent work with approaches like recombinant mutants and X-ray crystallography has given much new information about the ligand-binding properties of human serum albumin (HSA). The information increases the understanding of this unique transport and depot protein and could give a structural basis for the possible construction of therapeutic agents with altered HSA-binding properties. A tabulation of high-affinity binding sites for both endogenous and exogenous compounds has been made; it could be useful for the above-mentioned purpose, but it could also be of value when trying to predict potential drug interactions at the protein-binding level. Drug displacement is not always a complication to therapy; it can be used to increase the biological effect of a drug. However, due to rebinding at other sites, the increase in the free concentration of a displaced ligand can be less than expected. Drugs and drug metabolites can also interact covalently with HSA; thiol-containing drugs often bind to the single free cysteine residue of HSA, and glucuronidated drugs react irreversibly with other residues of the protein. Reversible binding of ligands is often stereospecific, and therefore immobilized HSA can be used to separate drug isomers. Albumin-containing dialysates are useful for extracorporeal removal of endogenous toxins and in the treatment of drug overdoses. HSA has different types of hydrolytic activities, which also can be stereospecific. The esterase-like property seems especially useful in converting prodrugs to active drugs in plasma.

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“…Conformational changes in the 313-to-365 region of albumin are thought to account for diminished binding, whereas an increase in affinity for binding of warfarin has been found for in vitro recombinant mutants of albumin, such as His242Glu and Lys199Ala, while for Try214Ala and Arg218His a small decrease in affinity was observed (272). The last substitution may also alter the pharmacokinetics of warfarin, since the free-drug concentration in individuals homozygous for Arg218His is expected to be elevated, resulting in a reduction in the serum half-life (201). As most of the antifungal agents are highly protein bound, albumin SNPs may affect antifungal-drug disposition.…”

Section: Distributionmentioning

confidence: 99%

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

2006

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SUMMARY Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion.

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Familial dysalbuminemic hyperthyroxinemia may result in altered warfarin pharmacokinetics

Cited by 35 publications

References 23 publications

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

Practical Aspects of the Ligand-Binding and Enzymatic Properties of Human Serum Albumin.

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

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