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https://hdl.handle.net/2440/77221
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dc.contributor.author | Maddison, J. | - |
dc.contributor.author | Somogyi, A. | - |
dc.contributor.author | Jensen, B. | - |
dc.contributor.author | James, H. | - |
dc.contributor.author | Gentgall, M. | - |
dc.contributor.author | Rolan, P. | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | British Journal of Clinical Pharmacology, 2013; 75(1):208-216 | - |
dc.identifier.issn | 0306-5251 | - |
dc.identifier.issn | 1365-2125 | - |
dc.identifier.uri | http://hdl.handle.net/2440/77221 | - |
dc.description.abstract | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS: Using unequivocally pure (R)- and (S)-warfarin we have demonstrated that (R)-warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin. The extent of the interaction is dependent on VKORC1 genotype. AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUCPT((R)-warfarin) : AUCPT((S)-warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype. | - |
dc.description.statementofresponsibility | John Maddison, Andrew A. Somogyi, Berit P. Jensen, Heather M. James, Melanie Gentgall and Paul E. Rolan | - |
dc.language.iso | en | - |
dc.publisher | Blackwell Publishing Ltd | - |
dc.rights | © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society | - |
dc.source.uri | http://dx.doi.org/10.1111/j.1365-2125.2012.04335.x | - |
dc.subject | Pharmacodynamics | - |
dc.subject | pharmacogenetics | - |
dc.subject | pharmacokinetics | - |
dc.subject | (R)-warfarin | - |
dc.subject | VKORC1 | - |
dc.subject | warfarin | - |
dc.title | The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1111/j.1365-2125.2012.04335.x | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Maddison, J. [0000-0001-8692-8878] | - |
dc.identifier.orcid | Somogyi, A. [0000-0003-4779-0380] | - |
Appears in Collections: | Aurora harvest 4 Pharmacology publications |
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