Enantioselective drug–protein interaction between mexiletine and plasma protein

Yu, Lushan; Hong, Yanjun; Li, Li; Jin, Yingxiu; Zheng, Mingyue; Jiang, Hualiang; Zeng, Su

doi:10.1111/j.2042-7158.2012.01487.x

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…In particular, the (R)-enantiomer presented a downfield sense of the 1 H NMR signal non-equivalence, in agreement with what observed for the other studied mexiletine analogues [32]. Actually, recent studies showed that the binding of mexiletine enantiomers to human serum proteins was enantioselective [33,34]. Herein, we synthesized nonracemic MHM enantiomers as tools that can be used to study the enantioselectivity of this class of voltage-gated sodium channel blockers.…”

Section: Resultssupporting

confidence: 84%

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Catalano

Carocci²,

Lentini³

et al. 2013

DML

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m-Hydroxymexiletine (MHM) is a metabolite of mexiletine, a well known class IB anti-arrhythmic drug, which presents almost twice the activity of the parent compound on cardiac voltage-gated sodium channels. Given the different activity of mexiletine enantiomers on sodium currents (being the R-isomer the eutomer), it is conceivable that (R)- and(S)-MHM could differ in pharmacodynamic and pharmacokinetic properties, too. Herein we report the efficient synthesis of MHM enantiomers that could represent useful tools for further investigations on stereospecific requirements of the voltage-gated sodium channel binding site. MHM enantiomers and all the homochiral intermediates were fully characterized. The ee values for (R)- and (S)-MHM were >99%, as assessed by capillary electrophoresis using β-cyclodextrin sulfated sodium salt as a chiral selector.

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Section: Resultssupporting

confidence: 84%

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Catalano

Carocci²,

Lentini³

et al. 2013

DML

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“…Plasma protein binding studies were conducted using an ultra filtration technique (Yu et al ., ). Briefly, freshly collected rat blank plasma samples were spiked with 20 μg·mL −1 of racemic warfarin with and without ETV (25 μg·mL −1 ).…”

Section: Methodsmentioning

confidence: 97%

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

John

John²,

Wu³

et al. 2013

British J Pharmacology

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Warfarin is often used with etravirine (ETV) to prevent HIV-related thromboembolic events. As both warfarin and ETV bind to plasma proteins and are metabolized by hepatic cytochrome P450s, they are likely to interact. Hence, we evaluated the effect of ETV on the pharmacokinetics and blood clotting time of racemic warfarin in rats. EXPERIMENTAL APPROACHTwo groups of male Sprague-Dawley rats, in which the jugular vein had been cannulated, were studied. The control group (n = 10) received 1 mg·kg -1 racemic warfarin i.v., and the test group (n = 13) 1 mg·kg -1 of racemic warfarin followed by 25 mg·kg -1 ETV i.v. Serial blood samples were collected for up to 144 h and the blood clotting time (calculated as international normalized ratio [INR]) measured in blood plasma at each sample point. Plasma concentrations of R-warfarin, S-warfarin, R-7-hydroxywarfarin and S-7-hydroxywarfarin were measured by a LC/MS/MS method using a chiral lux cellulose-1 column. Pharmacokinetic parameters were analysed using non-compartmental methods. KEY RESULTSETV significantly increased, by threefold, the systemic clearance and volume of distribution of S-warfarin, but not those of R-warfarin. ETV decreased the total AUC of warfarin, but had no effect on its elimination half-life. ETV also increased the systemic clearance of both R-7-hydroxywarfarin and S-7-hydroxywarfarin but only increased the volume of distribution of R-7-hydroxywarfarin. Interestingly, the effect of warfarin on blood clotting time (INR) was significantly increased in the presence of etravirine. CONCLUSION AND IMPLICATIONSOur data suggest that etravirine may potentiate the anticoagulant effect of warfarin and this could have clinical significance. Abbreviations

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“…Monti et al combined molecular mechanisms (MM) and molecular dynamics (MD) with circular dichroism (CD) to identify the main interactions between ketoprofen enantiomers and the surrounding amino acids at short distances in bovine serum albumin 51 . Similarly, Yu et al took advantage of MM and MD to identify several key residues that are involved in the enantioselectivity for the binding of AGP to mexiletine enantiomers, such as Arg90 43 .…”

Section: Methods and Modelsmentioning

confidence: 99%

Stereoselective binding of chiral drugs to plasma proteins

et al. 2013

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Chiral drugs show distinct biochemical and pharmacological behaviors in the human body. The binding of chiral drugs to plasma proteins usually exhibits stereoselectivity, which has a far-reaching influence on their pharmacological activities and pharmacokinetic profiles. In this review, the stereoselective binding of chiral drugs to human serum albumin (HSA), α1-acid glycoprotein (AGP) and lipoprotein, three most important proteins in human plasma, are detailed. Furthermore, the application of AGP variants and recombinant fragments of HSA for studying enantiomer binding properties is also discussed. Apart from the stereoselectivity of enantiomer-protein binding, enantiomer-enantiomer interactions that may induce allosteric effects are also described. Additionally, the techniques and methods used to determine drug-protein binding parameters are briefly reviewed.

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Enantioselective drug–protein interaction between mexiletine and plasma protein

Abstract: hAGP may be one of the key proteins leading to the enantioselective protein bindings of mexiletine in human plasma (R>S). The residues Arg90, Leu79, Ser89 and Phe89 of hAGP may have important roles in the observed enantioselectivity.

Cited by 9 publications

References 34 publications

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Stereospecific Synthesis of m-Hydroxymexiletine Enantiomers

Effects of etravirine on the pharmacokinetics and pharmacodynamics of warfarin in rats

Stereoselective binding of chiral drugs to plasma proteins

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