Interaction of sulphinpyrazone with warfarin

Miners, John O.; Foenander, T.; Wanwimolruk, Sompon; Gallus, Alexander; Birkett, D. J.

doi:10.1007/bf00548401

Cited by 27 publications

(13 citation statements)

References 20 publications

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“…Causes include nonadherence to therapy; drug-drug interactions; genetic polymorphism of VKORC1 and CYP2C9; and consumption of foods high in vitamin K. In the current case, the area under the plasma rac-warfarin AUC over a 21 mg dosage interval was 175 mg h/l and the apparent oral clearance was 0.12 l/h. This is comparable to the mean CL p /F (0.16 l/h) measured in patients in a previous study that used the same assay [7], but the mean C p was approximately five times higher than that observed for a warfarin dose of 5 mg/day. This established that the patient was compliant with warfarin treatment and had 'normal' warfarin clearance.…”

Section: Resultssupporting

confidence: 86%

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Warfarin resistance associated with genetic polymorphism of VKORC1

Lewis

Nair

Heran

et al. 2016

Pharmacogenetics and Genomics

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The variable response to warfarin treatment often has a genetic basis. A protein homology model of human vitamin K epoxide reductase, subunit 1 (VKORC1), was generated to elucidate the mechanism of warfarin resistance observed in a patient with the Val66Met mutation. The VKORC1 homology model comprises four transmembrane (TM) helical domains and a half helical lid domain. Cys132 and Cys135, located in the N-terminal end of TM-4, are linked through a disulfide bond. Two distinct binding sites for warfarin were identified. Site-1, which binds vitamin K epoxide (KO) in a catalytically favorable orientation, shows higher affinity for S-warfarin compared with R-warfarin. Site-2, positioned in the domain occupied by the hydrophobic tail of KO, binds both warfarin enantiomers with similar affinity. Displacement of Arg37 occurs in the Val66Met mutant, blocking access of warfarin (but not KO) to Site-1, consistent with clinical observation of warfarin resistance.

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Section: Resultssupporting

confidence: 86%

“…Rac-warfarin concentrations were measured using a high-performance liquid chromatographic (HPLC) assay established in this laboratory [7]. The mean warfarin plasma concentration (C p ) was calculated as follows:…”

Section: Sample Collection and Analysis Of Plasma Warfarin Concentratmentioning

confidence: 99%

Warfarin resistance associated with genetic polymorphism of VKORC1

Lewis

Nair

Heran

et al. 2016

Pharmacogenetics and Genomics

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“…CYP2C9 is the second most abundantly expressed CYP in human liver and intestine. It has been estimated that CYP2C9 metabolizes approximately 16% of clinically prescribed drugs [28]. Like in case of CYP3A4, PXR, CAR, VDR, HNF4 and GR have been implicated in regulating CYP2C9 expression [6,29,30].…”

Section: Brief Overview Of Families Cyp1 Cyp2 and Cyp3 And Mechanismmentioning

confidence: 99%

Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues

Pávek

Dvořák

2008

CDM

288

198

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Numerous members of the cytochrome P450 (CYP) superfamily are induced after exposure to a variety of xenobiotics in human liver. We have gained considerable mechanistic insights into these processes in hepatocytes and multiple ligand-activated transcription factors have been identified over the past two decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic metabolism are also expressed in a range of extrahepatic tissues (e.g. intestine, brain, kidney, placenta, lung, adrenal gland, pancreas, skin, mammary gland, uterus, ovary, testes and prostate). Since the expression of the majority of the isoforms appears to be very low in the extrahepatic tissues in comparison with predominant expression in adult liver, the role of the enzymes in overall biotransformation and total body clearance is minor. However, basal expression and up-regulation of extrahepatic CYP enzymes can significantly affect local disposition of xenobiotics or endogenous compounds in peripheral tissues and thus modify their pharmacological/toxicological effects or affect absorption of xenobiotics into systemic circulation. The goal of this review is to critically examine our current understanding of molecular mechanisms involved in induction of xenobiotic metabolizing CYP genes of human families CYP1, CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues. We concentrate on organs such as the intestine, kidney, lung, placenta and skin, which are involved in drug distribution and clearance or are in direct contact with environmental xenobiotics. We also discuss single nucleotide polymorphisms (SNPs) of key CYPs, which at the level of transcription affect expression of the genes in the extrahepatic tissues or are associated with some pathophysiological stages or disorders in the organs.

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“…A MEKC method has recently been developed for the kinetic study of the reaction of the cytochrome P450 2C9 isoform (CYP2C9) with diclofenac as a probe substrate 8. Although CYP2C9, one of the most important isoforms in the human liver, constitutes about 20% of total human liver CYP and metabolizes approximately 10% of therapeutically important drugs 9, 10, diclofenac is a widely used nonsteroidal anti‐inflammatory drug which acts as a potent inhibitor of prostaglandin endoperoxide synthase 11. The major primary diclofenac metabolite is 4′‐hydroxydiclofenac, with 3′‐hydroxy‐ and 5‐hydroxydiclofenac being minor metabolites.…”

Section: Introductionmentioning

confidence: 99%

Study of atypical kinetic behaviour of cytochrome P450 2C9 isoform with diclofenac at low substrate concentrations by sweeping‐MEKC combination

Řemínek

Glatz

2010

J of Separation Science

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In view of the fact that several studies have shown that diclofenac hydroxylation by cytochrome P450 2C9 deviated from Michaelis-Menten kinetics at low substrate concentrations, sweeping combined with MEKC was applied for the kinetic study of this pharmacologically important reaction. A 50 μm fused silica capillary (56 cm effective length) was used to carry out all separations. 70 mM SDS in 20 mM phosphate 20 mM tetraborate buffer, pH 8.6, was used as the BGE. Injection was accomplished by the application of 50 mbar (5 kPa) pressure to the sample vial for 52 s. Separation was performed at 22 kV (positive polarity), with a capillary temperature of 25°C and detection at 200 nm. The higher sensitivity of the sweeping-MEKC combination compared with the simple MEKC method enabled this reaction to be fitted to a Hill kinetic model and confirmed the findings of other authors. A Michaelis constant of 2.91±0.10 μM, maximum reaction velocity of 9.16±0.16 nmol/min/nmol and Hill coefficient of 1.66±0.08 were determined. This value of Hill coefficient confirms the presence of a positive cooperativity at low diclofenac concentrations and supports the hypothesis of two substrates binding at or near the active site.

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Interaction of sulphinpyrazone with warfarin

Cited by 27 publications

References 20 publications

Warfarin resistance associated with genetic polymorphism of VKORC1

Warfarin resistance associated with genetic polymorphism of VKORC1

Xenobiotic-Induced Transcriptional Regulation of Xenobiotic Metabolizing Enzymes of the Cytochrome P450 Superfamily in Human Extrahepatic Tissues

Study of atypical kinetic behaviour of cytochrome P450 2C9 isoform with diclofenac at low substrate concentrations by sweeping‐MEKC combination

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