Effect of Ethanol on the Binding of Warfarin Enantiomers to Human Serum Albumin

Tatsumi, Akitoshi; Kadobayashi, Muneo; Iwakawa, Seigo

doi:10.1248/bpb.30.826

Cited by 13 publications

(8 citation statements)

References 21 publications

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“…15) Our previous study suggested that ethanol changes the binding of warfarin enantiomer to human serum albumin stereoselectively. 9) However, that study was performed 2.9% (500 mM) of ethanol. The present study indicated that ethanol affected warfarin metabolism by CYP2C9.1.…”

Section: Discussionmentioning

confidence: 99%

“…8) Our previous study suggested that ethanol changes the binding of warfarin enantiomer to human serum albumin stereoselectively. 9) Acute intoxication by alcohol reduces the metabolism of warfarin by CYPs, causing increased anticoagulant effects, and leading to a risk of hemorrhage. 10) Conversely, chronic alcohol ingestion might enhance metabolic enzyme activity, leading to a decrease in the anticoagulant effects of warfarin.…”

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confidence: 99%

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Effect of Ethanol on S-Warfarin and Diclofenac Metabolism by Recombinant Human CYP2C9.1

Tatsumi

Ikegami

Morii

et al. 2009

Biological & Pharmaceutical Bulletin

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Warfarin, which consists of a racemic mixture of S-and Renantiomer, has been used as an anticoagulant agent. The anticoagulant activity of S-warfarin is 3-5 times greater than that of R-warfarin.1) This drug has a narrow therapeutic index and shows marked drug-drug interactions when coadministered with other agents that alter warfarin metabolism.2,3) The stereoselective metabolism of warfarin enantiomers in humans has been shown to be catalyzed by cytochrome P450 (CYP) such as CYP1A1/2, 2C9, and 3A4. 4,5) The 7-hydroxylation of S-warfarin is exclusively catalyzed by CYP2C9. RWarfarin is metabolized primarily by CYP1A2 to 6-and 8-hydroxywarfarin, and by CYP3A4 to 10-hydroxywarfarin. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), is also metabolized to 4Ј-hydroxydiclofenac by CYP2C9. 6,7)Ethanol is widely used as a pharmaceutical excipient for the solubilization of many hydrophobic drugs. Various drugs can pharmacokinetically or pharmacodynamically interact with alcohol. 8) Our previous study suggested that ethanol changes the binding of warfarin enantiomer to human serum albumin stereoselectively. 9) Acute intoxication by alcohol reduces the metabolism of warfarin by CYPs, causing increased anticoagulant effects, and leading to a risk of hemorrhage.10) Conversely, chronic alcohol ingestion might enhance metabolic enzyme activity, leading to a decrease in the anticoagulant effects of warfarin. Hamitouche et al. 11) showed that CYP2C9, as well as other CYPs such as CYP2E1, CYP1A2, and CYP3A4, is also able to metabolize ethanol, and indicated that these CYPs have a low affinity for ethanol for its metabolization. The apparent K m value determined for ethanol oxidation by various CYPs was around 10 mM. 11)Therefore, it is possible that ethanol affects the metabolism of other substrates by CYP2C9. Few studies on the effect of ethanol on warfarin metabolism by human CYP2C9 in vitro have been reported. The non-significant metabolic interaction of diclofenac (15 mM) with ethanol by CYP2C9 has been reported. 12) However, the effect of ethanol on the metabolism of diclofenac at lower concentrations by CYP2C9 has not been examined. In this paper, we have examined the effect of ethanol on the metabolism of S-warfarin and diclofenac by recombinant CYP2C9.1 microsomes (CYP2C9.1). MATERIALS AND METHODS Materials S-(Ϫ)-Warfarin, diclofenac sodium, ethanol, naproxen, NADPϩ , glucose-6-phosphate, MgCl 2 · 6H 2 O, and glucose-6-phosphate dehydrogenase were purchased from Wako Pure Chemical Ind. (Osaka, Japan). 4Ј-Hydroxydiclofenac was purchased from Sigma-Aldrich (MO, U.S.A.). 7-Hydroxywarfarin and human CYP2C9.1ϩP450 reductase microsomes derived from baculovirus expression systems were purchased from BD Gentest (MA, U.S.A.). All other chemicals and solvents were of analytical grade or higher.Inhibition Study According to the method of Iwakawa et al., 13) a metabolic inhibition study was performed. The time of incubation and concentration of microsomal protein in the study were determined to be in a linear range for ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effect of Ethanol on S-Warfarin and Diclofenac Metabolism by Recombinant Human CYP2C9.1

Tatsumi

Ikegami

Morii

et al. 2009

Biological & Pharmaceutical Bulletin

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“…Previously, we suggested that ethanol (2.9 vol%; 500 mM) changes the binding of warfarin enantiomer to HSA stereoselectively, and ethanol decreases the dissociation constant of S-warfarin but increase the dissociation constant of R-warfarin. 17) We also suggested that ethanol of 0.1 vol% or higher inhibits S-warfarin metabolism by recombinant human CYP2C9.1 and 3 vol% ethanol inhibits diclofenac metabolism by the CYP2C9.1. 18) However, studies on the effect of ethanol on the hydrolysis of ester-type drugs by HSA have been limited.…”

Section: 2)mentioning

confidence: 88%

The Effect of Ethanol on the Hydrolysis of Ester-Type Drugs by Human Serum Albumin

Tatsumi

Inoue

Hamaguchi

et al. 2018

Biological & Pharmaceutical Bulletin

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Human serum albumin (HSA) has two major ligand-binding sites, sites I and II, and hydrolyzes compounds at both sites. Although the hydrolytic interaction of ester-type drugs with other drugs by HSA has been reported, there are only a few studies concerning the effect of pharmaceutical excipients on the hydrolysis of ester-type drugs by HSA. In the present study, we investigated the effect of ethanol (2 vol%; 345 mM) on the hydrolysis of aspirin, p-nitrophenyl acetate, and olmesartan medoxomil, which are ester-type drugs, with 4 different lots of HSA preparations. The hydrolysis activities of HSA toward aspirin, p-nitrophenyl acetate, and olmesartan medoxomil were measured from the pseudo-first-order degradation rate constant (k obs ) of salicylic acid, p-nitrophenol, and olmesartan, respectively, which are the HSA-hydrolyzed products. Ethanol inhibited hydrolysis of aspirin by HSA containing low levels of fatty acids, but not by fatty acid-free HSA. Ethanol inhibited hydrolysis of p-nitrophenyl acetate by both fatty acid-free HSA and HSA containing low levels of fatty acids. In contrast, the hydrolysis of olmesartan medoxomil by HSA was insignificantly inhibited by ethanol, but inhibited not only by warfarin and indomethacin but also by naproxen, which are site I binding drugs and a site II binding drug, respectively. These results suggest that the inhibitory action of ethanol on the hydrolysis of ester-type drugs by HSA differs between site I binding drugs and site II binding drugs.Key words human serum albumin; ethanol; hydrolysis; olmesartan medoxomil; aspirin; drug interaction Human serum albumin (HSA) is a monomeric, 585-residue protein, and contains three structurally similar α-helical domains (I-III); each domain is divided into subdomains A and B, which contain six and four α-helices, respectively.

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“…However, chronic liver disease itself can increase bleeding due to its negative effect on vitamin K-dependant clotting factors. 36 No attempt was made in this audit to assess whether practitioners considered alcohol to have a negative or positive effect on the INR.…”

Section: Factors Affecting the Inrmentioning

confidence: 99%

Management of patients on warfarin by general dental practitioners in South West Wales: continuing the audit cycle

2009

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Effect of Ethanol on the Binding of Warfarin Enantiomers to Human Serum Albumin

Cited by 13 publications

References 21 publications

Effect of Ethanol on S-Warfarin and Diclofenac Metabolism by Recombinant Human CYP2C9.1

Effect of Ethanol on S-Warfarin and Diclofenac Metabolism by Recombinant Human CYP2C9.1

The Effect of Ethanol on the Hydrolysis of Ester-Type Drugs by Human Serum Albumin

Management of patients on warfarin by general dental practitioners in South West Wales: continuing the audit cycle

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