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 urine samples. The fractions unbound of warfarin enantiomers were determined using equilibrium dialysis. 3. Wide variability was observed in daily dose requirements (mean 6.1 mg; range: 2.5‐12 mg), in plasma concentrations of (S)‐ warfarin (0.48 mg l(‐1); 0.11‐1.02 mg l(‐1)), (R)‐warfarin (0.87 mg l(‐ 1); 0.29‐1.82 mg l(‐1)), (R,S)‐warfarin alcohol (0.31 mg l(‐1); 0.02‐ 0.72 mg l(‐1)) and (S)‐7‐hydroxywarfarin (0.25 mg l(‐1); 0.07‐0.37 mg l(‐1)) and the percentage unbound of (S)‐warfarin (0.53%; 0.29%‐0.82%) and (R)‐warfarin (0.54%; 0.26%‐0.96%). 4. The mean plasma clearances of warfarin enantiomers were 7.5 1 day‐1 per 70 kg (2.5‐22.1) for (S)‐ warfarin and 3.6 1 day‐1 per 70 kg (1.6‐8.8) for (R)‐warfarin. There was a significant correlation between the estimated formation clearance of (S)‐7‐hydroxywarfarin and the clearance of (S)‐warfarin, which accounted for much of the variability in the latter.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose

“…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.…”

“…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:…”

“…3 Owing to the more extensive metabolism of the S-enantiomer than the R-enantiomer, its plasma concentrations are approximately two-fold lower than that of the R-enantiomer. 4 Genetic polymorphisms of the CYP2C9 gene, which give rise to proteins with altered catabolic activity, have been described. The two most common variant alleles in Caucasian populations are CYP2C9*2 with a point mutation in exon 3 causing Arg 144 Cys exchange and CYP2C9*3 with a point mutation in exon 7 causing Ile 359 Leu exchange.…”

Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin

“…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.…”

Warfarin Enantiomers Pharmacokinetics by CYP2C19

“…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).…”