1994
DOI: 10.1111/j.1365-2125.1994.tb04305.x
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Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac‐warfarin [see comments]

Abstract: 1. The disposition of warfarin enantiomers and metabolites has been studied in 36 patients receiving chronic rac‐warfarin therapy, titrated to approximately the same anticoagulant response. 2. A stereoselective h.p.l.c. assay was employed to determine the concentrations of (R)‐ and (S)‐warfarin, (R,S)‐warfarin alcohol and (S)‐7‐hydroxywarfarin in plasma and 24 h urine samples. The concentrations of (R)‐7‐ hydroxywarfarin, (S,S)‐warfarin alcohol and (R)‐6‐ and (S)‐6‐ hydroxywarfarin were also determined in urin… Show more

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Cited by 93 publications
(69 citation statements)
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“…This is in concordance with studies demonstrating a higher intrinsic sensitivity to the anticoagulant effect of warfarin in elderly patients. 4,24,25 As expected, no significant difference in R-warfarin clearance was found when the patients with a different genotype were compared (one-way ANOVA). In our multiple regression model, the two factors that influenced R-warfarin clearance the most were cotreatment with warfarin metabolism inducers and age.…”
Section: Discussionmentioning
confidence: 90%
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“…This is in concordance with studies demonstrating a higher intrinsic sensitivity to the anticoagulant effect of warfarin in elderly patients. 4,24,25 As expected, no significant difference in R-warfarin clearance was found when the patients with a different genotype were compared (one-way ANOVA). In our multiple regression model, the two factors that influenced R-warfarin clearance the most were cotreatment with warfarin metabolism inducers and age.…”
Section: Discussionmentioning
confidence: 90%
“…Owing to the long elimination half-lives of R-and S-warfarin, around 40 and 25 h, respectively, 22 the warfarin concentration measured in this period approximates the average steady-state concentration (C SS ). 4,30,31 Steady-state and drug compliance was assumed in all the patients. Since warfarin bioavailability is almost complete, F was set to unity and clearance could be estimated using the following equation:…”
Section: Pharmacokinetic Analysismentioning
confidence: 99%
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“…The simulation was performed assuming that the representative patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*3/*3 genotypes had the total oral clearance for (S)-warfarin of 0.34, 0.11 and 0.034 l/h, respectively, 7.4 l for volume of distribution and an oral bioavailability of unity. The horizontal broken line represents the population mean value for the steady-state plasma (S)-warfarin concentration with an oral warfarin dose of 6.1 mg/day in Caucasians 53 and the solid line represents that with 3.4 mg/day in Japanese patients. CYP2C9 polymorphisms and warfarin therapy H Takahashi and H Echizen much higher than those with the wildtype genotype and thereby elicit a more extensive depletion of vitamin K-dependent coagulation proteins particularly F-VII with a short t 1/2 of 1.5-5 h.…”
Section: Risks Of Adverse Drug Reactionsmentioning
confidence: 99%
“…1), however S-warfarin is 3-5 times more potent than R-enantiomer. Both enantiomers are extensively metabolized in the liver (Chan E et al, 1994;Takahashi H and Echizen H, 2001). The more potent S-enantiomer is metabolized mainly to S-7-hydroxywarfarin by CYP2C9, whereas R-enantiomer is metabolized to R-6, R-7, R-8 and R-10-hydroxywarfarin by several CYPs involving CYP1A2, CYP3A4 and CYP2C19 (Kaminsky LS and Zhang ZY, 1997).…”
Section: Introductionmentioning
confidence: 99%