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PubMed2001

Effect of ubidecarenone on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats.

Interaction between the antioxidant ubidecarenone and the oral anticoagulant warfarin enantiomers was investigated in rats. The decreased hypoprothrombinemic response, assessed by means of percent changes of prothrombin complex activity and clotting factor VII activity, to warfarin, was observed following oral administration of 1.5 mg/kg racemic warfarin to rats during an 8-day oral regimen (10 mg/kg daily) of ubidecarenone. The antioxidant had no apparent effect on the in vitro rat serum protein binding of warfarin enantiomers. Treatment with ubidecarenone did not affect the absorption and distribution of the S- and R-enantiomers of warfarin, but produced a significant increase in the total serum clearance values of both R- and S-warfarin in rats. This effect was more pronounced with R-warfarin than with S-warfarin. The increased clearance values are attributable to acceleration of certain metabolic pathways and renal excretion of the warfarin enantiomers.

Animals↗
PubMed1997

Effect of fixed minidose warfarin, conventional dose warfarin and aspirin on INR and prothrombin fragment 1 + 2 in patients with atrial fibrillation.

The efficacy of conventional dose adjusted oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation is well-documented but not considered ideal as primary antithrombotic treatment in elderly patients. The antithrombotic effect of fixed minidose warfarin 1.25 mg/day alone or in combination with aspirin 300 mg/day, of conventional dose adjusted warfarin (INR 2.0-3.0), and of aspirin 300 mg/day have been investigated in outpatients with chronic nonvalvular atrial fibrillation in the second Copenhagen Atrial Fibrillation, Aspirin and Anticoagulant Therapy Study (AFASAK 2). In order to investigate the effect on the coagulation system of the treatments, the International Normalized Ratio of the prothrombin time (INR) and prothrombin fragment 1 + 2 (F1 + 2) were monitored at baseline and after three months of treatment in 100 patients consecutively included in the trial. At baseline no differences in INR and F1 + 2 between the four treatment groups were present. After three months of therapy the level of INR increased significantly from baseline in patients receiving warfarin in any dose and the level of F1 + 2 decreased significantly by combined minidose warfarin-aspirin and by dose adjusted warfarin. When comparing the changes over time in F1 + 2 (three-month value minus baseline value) during therapy with fixed minidose warfarin, combined minidose warfarin-aspirin and aspirin alone no significant difference between the groups was found. In conclusion, INR was changed by all three warfarin regimens but only dose adjusted warfarin (INR 2.0-3.0) had a marked effect on F1 + 2.

Aged↗
PubMed1997

Warfarin and epistaxis: should warfarin always be discontinued?

The object of this study was to determine whether warfarin could be safely continued in patients with epistaxis if the International Normalized Ratio (INR) was within the suggested therapeutic range. Twenty patients on warfarin treatment were compared with controls, matched for age and sex. Local measures for the control of epistaxis were undertaken appropriately in all the patients. In the warfarin group 17 patients (85%) did not discontinue warfarin as the INR was within the suggested range. There were no additional bleeding complications or failure of epistaxis control due to continuation of warfarin. There was no significant difference in the mean hospital stay between the warfarin and non-warfarin groups. It is concluded that warfarin can be continued safely in patients with epistaxis, in appropriate circumstances, and that the policy of stopping warfarin routinely in all patients with epistaxis should be reconsidered.

Aged↗
PubMed2003

Comparative pharmacokinetics of coumarin anticoagulants L: Physiologic modeling of S-warfarin in rats and pharmacologic target-mediated warfarin disposition in man.

The anticoagulant warfarin exemplifies a type of drug that exhibits high affinity to pharmacologic target sites of limited capacity, resulting in unusual concentration-dependent distribution and elimination properties. The time course of warfarin concentrations in the serum, liver, kidneys, muscle, and abdominal fat of male Sprague-Dawley rats was determined by high-performance liquid chromatography after IV injection of a 0.25 or 1.0 mg/kg dose. The rats were preclassified on the basis of their serum free fraction of warfarin; animals with free fraction values of approximately 0.004 and 0.01 and corresponding differences in elimination half-life were selected for study, yielding four experimental groups. Several rats of each group were sacrificed periodically over approximately 80-240 h for determination of drug concentrations. S-warfarin concentrations in serum declined apparently exponentially over at least one order of magnitude. During this time, concentrations in all other assayed tissues declined much more slowly. In another experiment, S-warfarin concentrations in serum and liver were followed for approximately 50 days after IV injection of a 1 mg/kg dose. This revealed a terminal, very slow elimination phase in serum nearly parallel to the decline in liver drug concentrations. Simultaneous physiologic modeling of all data (30 equations) using ADAPT II (Biomedical Simulations Resource, Los Angeles, CA), with intrinsic clearance, the dissociation constant of the warfarin-high affinity binding site complex, and two binding parameters for the (unassayed) remainder tissue compartment as parameters of unknown value, yielded very good fittings and parameter estimates with relatively small standard deviations. The unusual dose-dependent accumulation characteristics of this type of drug during continuous infusion are demonstrated by computer simulation of published results of warfarin infusions in rats. Utilization of a model premised on similar target-mediated drug disposition also allowed characterization of data from the literature for racemic warfarin pharmacokinetics in man.

Adipose Tissue↗
PubMed1987

Warfarin resistance. Vitamin K epoxide reductase of Scottish resistance genes is not irreversibly blocked by warfarin.

The dithiothreitol-dependent vitamin K 2,3 epoxide (vitamin KO) reductase activity in liver microsomes of Scottish-derived warfarin-resistant Wistar rats (Tolworth Laboratory) was compared to that of susceptible Wistar rats. Under the test conditions, reductase activities in liver homogenates and in liver microsomes were comparable for both strains. The in vitro i50 of S-warfarin for microsomal reductase activity was 1 to 2 microM in both strains. The effect of in vivo S-warfarin was investigated after single doses, i.e. 0.2 and 1 mg/kg for the susceptible rats, and 1 and 5 mg/kg for the resistant rats. At 20 hr following the warfarin administrations in the susceptible strain, microsomal reductase was suppressed to about 30% of control. Microsomal reductase activity in the resistant strain was not reduced. Tissue and microsomal warfarin concentrations, however, were comparable in both strains. Wash experiments with microsomes which were treated in vitro with S-warfarin showed that vitamin KO reductase of the warfarin-resistant strain was not irreversibly inactivated by warfarin. The reactivation was mediated by DDT. The results suggest the following characteristic of the vitamin KO reductase of the Scottish resistance gene: contrary to the "normal" enzyme, the tight complex between the inhibitor and the resistant enzyme is liable to reactivation by reduction of the disulfide bridge in the active centre of the enzyme. This property explains the resistance for 4-hydroxycoumarin anticlotting activity.

Animals↗
PubMed2000

Validation of a method for the determination of (R)-warfarin and (S)-warfarin in human plasma using LC with UV detection.

A sensitive and selective chiral high-performance liquid chromatography (HPLC) method was developed for the determination of (R)-warfarin and (S)-warfarin in human plasma. (R)- and (S)-warfarin and the internal standard (oxybenzone) were extracted from human plasma that had been made acidic with 1 N sulfuric acid into ethyl ether. The ethyl ether layer was removed and evaporated, and the residue was reconstituted in 200 microl of acetonitrile. A 50-microl aliquot was injected onto the HPLC system. Separation was achieved on a beta-cyclodextrin column (250 x 4.6 mm, 5 microm) with a mobile phase composed of acetonitrile:glacial acetic acid:triethylamine (1000:3:2.5, v/v/v). Detection was by ultraviolet absorbance at 320 nm. Late-eluting peaks were diverted from the analytical column by using a beta-cyclodextrin precolumn (50 x 4.6 mm, 5 microm) and a column switching device. The retention times of (R)- and (S)-warfarin and the internal standard were approximately 7.7, 6.9 and 4.0 min, respectively. The run time was 15 min. The assay was linear in concentration ranges of 12.5-2500 ng/ml for (R)- and (S)-warfarin in human plasma. The analysis of quality control samples for (R)- and (S)-warfarin (25.0, 400 and 2000 ng/ml) demonstrated excellent precision with relative standard deviations (R.S.D.) for (R)-warfarin of 10.9, 2.8, and 2.8%, respectively (n = 18), and for (S)-warfarin of 7.0, 2.4 and 2.6%, respectively (n = 18). The method was accurate with all overall (n = 18) mean concentrations being less than 6.0% from nominal at all quality control sample concentrations.

Chromatography, High Pressure Liquid↗
PubMed1994

Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients.

OBJECTIVE: The aim of the study was to compare the incidence of bleeding complications in patients receiving warfarin alone and those receiving warfarin in combination with acetylsalicylic acid. SUBJECTS AND METHODS: This retrospective study comprises all outpatients in our hospital receiving warfarin (n = 3166) in the period 1 January 1986 to 31 December 1990. Of these, 2026 patients received warfarin alone, aiming at an international normalized ratio level of 4.2-2.5, whereas the combination of warfarin and acetylsalicylic acid (150 mg daily) was given to 1140 patients, aiming at an international normalized ratio level of 2.8-2.2. Total observation time represents 4420 treatment years. RESULTS: A total of 175 bleeding episodes was observed, 18 of which were fatal, and 96 were serious (requiring hospitalization). The incidence of minor bleedings was significantly higher in the combined therapy group than in the group receiving warfarin alone, 2.9% and 1.4% respectively (P < 0.003). However, there was no difference in the therapy groups regarding the incidence of serious and fatal bleedings. The overall incidence of gastrointestinal bleedings and was equal to the two groups. CONCLUSIONS: The combination of warfarin and aspirin 150 mg daily aiming at a less intense level of anticoagulation than in warfarin therapy alone does not increase the risk of major or fatal haemorrhage.

Adolescent↗
PubMed1995

The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats.

The effects of Danshen (Salvia miltiorrhiza), a popular traditional Chinese medicinal herb on the pharmacokinetics and pharmacodynamics of R- and S-warfarin stereoisomers were studied in rats. After a single oral dose of racemic warfarin (2 mg kg-1), treatment with oral Danshen extract (5 g kg-1, twice daily) for 3 days significantly altered the overall pharmacokinetics of both R- and S-warfarin and increased the plasma concentrations of both enantiomers over a period of 24 h and the prothrombin time over 2 days. At steady-state levels of racemic warfarin (0.2 mg kg-1 day-1 for 5 days) the 3-day treatment of Danshen extract (5 g kg-1, twice daily) not only prolonged the prothrombin time but also increased the steady-state plasma concentrations of R- and S-warfarin. The results indicate that Danshen extracts can increase the absorption rate constant, area under plasma concentration-time curves, maximum concentrations and elimination half-lives, but decreases the clearances and apparent volume of distribution of both R- and S-warfarin. The pharmacokinetic and pharmacodynamic interactions of warfarin during co-treatment with Danshen extract observed in this study indicate an explanation for the clinically observed incidents of exaggerated warfarin adverse effects when traditional Chinese medicinal herbs or herbal products such as Danshen and Danggui (observed in a previous study) were co-administered.

Acenocoumarol↗
PubMed1983

Salivary excretion of warfarin in rabbits: relationship between pharmacological effect and salivary pharmacokinetics of warfarin in rabbits.

The salivary excretion of warfarin was investigated following intravenous and oral administration to rabbits. The salivary decay curves following intravenous injection (50 mg/kg) fitted to the two-compartment open model. On the other hand, following oral administration (100 mg/kg) the disposition of warfarin fitted to the one-compartment open model. There was a good linear relationship between the warfarin concentrations in saliva and plasma. The saliva vs. plasma (S/P) ratio was approximately 0.07. A good correlation was also observed between the warfarin concentrations in saliva and plasma protein-unbound fraction. The saliva vs. plasma protein-unbound fraction (S/Pf) ratio was approximately 0.92. Therefore, salivary concentration of warfarin corresponded with plasma free warfarin concentration. Furthermore, warfarin concentration in saliva was correlated with pharmacological effect, prothrombin complex activity. These results suggested that salivary warfarin concentration which was correlated with pharmacological effect had a possibility of utilization in pharmacokinetic studies and therapeutic drug monitoring.

Administration, Oral↗
PubMed1996

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

BACKGROUND: Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. METHODS: 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. FINDINGS: The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. INTERPRETATION: Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.

Aged↗
PubMed1991

Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin.

Inhibition of the metabolism of (S)-warfarin, the more pharmacologically active enantiomer of the racemic drug, by (R)-warfarin was investigated in microsomes obtained from three human livers. In each case the production of both (S)-6- and (S)-7-hydroxywarfarin was found to be competitively inhibited by (R)-warfarin. The KiS for inhibition of (S)-6- and (S)-7-hydroxylation by (R)-warfarin ranged from 7.0 to 8.4 microM and from 6.0 to 6.9 microM, respectively, while the KmS for the 6- and 7-hydroxylation of (S)-warfarin ranged from 3.6 to 3.8 microM and from 3.3 to 3.9 microM, respectively. In contrast, except for the 4'-hydroxylation pathway (S)-warfarin was found to be a weak inhibitor of the metabolism of (R)-warfarin. Possible implications of these findings include the following: (1) the kinetic parameters defining the interactions of two enantiomers of a racemic drug with the cytochrome P-450s or other macromolecular systems in the living organism can only be properly defined from experiments with the pure enantiomers, (2) an enantiomer of a racemic drug may contribute significantly to biological effect not by its inherent activity but by altering the pharmacokinetics of the eutomer, and (3) enantiomeric interactions are not easily detected unless directly sought and may be relatively common.

Aryl Hydrocarbon Hydroxylases↗
PubMedDate not supplied

Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions.

Previous kinetic studies have identified a high-affinity (S)-warfarin 7-hydroxylase present in human liver microsomes which appears to be responsible for the termination of warfarin's biological activity. Inhibition of the formation of (S)-7-hydroxywarfarin, the inactive, major metabolite of racemic warfarin in humans, is known to be the cause of several of the drug interactions experienced clinically upon coadministration of warfarin with other therapeutic agents. In order to identify the specific form(s) of human liver cytochrome P-450 involved in this particular toxicity, we have determined the metabolic profiles of 11 human cytochrome P-450 forms expressed in HepG2 cells toward both (R)- and (S)-warfarin. Of the 11 forms examined only 2C9 displayed the regioselectivity and stereoselectivity appropriate for the high-affinity human liver microsomal (S)-7-hydroxylase. We further compared Michaelis-Menten and sulfaphenazole inhibition constants for (S)-warfarin 7-hydroxylation catalyzed by cDNA-expressed 2C9 and by human liver microsomes. Similar kinetic constants were obtained for each enzyme source. It is concluded that 2C9 is likely to be a principal form of human liver P-450 which modulates the in vivo anticoagulant activity of the drug. It is further concluded that those drug interactions with warfarin that arise as a result of decreased clearance of the biologically more potent S-enantiomer may have as their common basis the inhibition of P-450 2C9.

Aryl Hydrocarbon Hydroxylases↗
PubMed2003

Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.

BACKGROUND: Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding. After three months of conventional warfarin therapy, a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism. METHODS: We conducted a randomized, double-blind study, in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years. RESULTS: Of 369 patients assigned to low-intensity therapy, 16 had recurrent venous thromboembolism (1.9 per 100 person-years), as compared with 6 of 369 assigned to conventional-intensity therapy (0.7 per 100 person-years; hazard ratio, 2.8; 95 percent confidence interval, 1.1 to 7.0). A major bleeding episode occurred in nine patients assigned to low-intensity therapy (1.1 events per 100 person-years) and eight patients assigned to conventional-intensity therapy (0.9 event per 100 person-years; hazard ratio, 1.2; 95 percent confidence interval, 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio, 1.3; 95 percent confidence interval, 0.8 to 2.1). CONCLUSIONS: Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism. The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding.

Age Factors↗
PubMed1989

No effect of terodiline on anticoagulation effect of warfarin and steady-state plasma levels of warfarin enantiomers in healthy volunteers.

The influence of terodiline (25 mg b.i.d.) on the anticoagulant effect and plasma levels of warfarin enantiomers was studied in 23 young healthy male volunteers. Racemic warfarin was first given for 24 days to determine the doses required for the subject's vitamin K-dependent coagulation factors to fall within 10-20% of the normal range, as determined by the Thrombotest. During continuous warfarin treatment (mean daily dose 5.3 mg, range 2.5-9.4 mg), terodiline or placebo was given for two weeks in a randomized and double-blind fashion, and then the drugs were crossed over and given for another two weeks. Terodiline did not influence the anticoagulant effect of warfarin or the plasma levels of the warfarin enantiomers. The results indicate that it should not be necessary to monitor patients on combined therapy with terodiline and warfarin more frequently than patients on warfarin monotherapy.

Adult↗
PubMed1991

Standardised initial warfarin treatment: evaluation of initial treatment response and maintenance dose prediction by randomised trial, and risk factors for an excessive warfarin response.

We report a comparison of warfarin treatment outcomes in 172 inpatients in two general hospitals randomly assigned to commence warfarin therapy by one of two methods; the first where warfarin dosage was determined using a flexible dose induction protocol, and the other where dosage was prescribed empirically by resident medical staff. The mean INR for each treatment day, the mean time to reach a therapeutic level of INR, the mean maintenance dose and the mean time to reach maintenance dose were not significantly different between the protocol and empirical treatment groups. Although the mean observations of warfarin effect were similar between the two groups, there were more patients with excessive warfarin effect (INR greater than 4.0) during empirical treatment. In addition, age and identified complicating factors such as interfering drugs, heart failure or alcohol abuse were significant predictors of excessive warfarin effect, regardless of treatment group. The protocol dose administered on day 4 of treatment, which has been used as a determinant of maintenance dose, predicted maintenance dose to within 1 mg in 57/83 patients (69%, 95% confidence interval: 59-79%). We conclude that as a method for safely and effectively initiating warfarin therapy, this protocol at least matches the empirical prescribing skills of medical staff in a teaching hospital.

Aged↗
PubMed2000

The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation.

The contribution of (R)- and (S)-warfarin enantiomers, vitamin K and vitamin K epoxide and patient factors to inter-individual variability in daily warfarin requirements were examined in a group of 73 patients. Simple correlation analysis showed a significant positive relationship between INR values and plasma (S)-warfarin concentrations (r = 0.25; p = 0.038). Multivariate analysis for relationships with INR demonstrated a highly significant positive relationship between INR and (S)-warfarin (p = 0.004) and plasma vitamin K epoxide concentrations (p = 0.028), and a significant negative relationship between INR and plasma vitamin K concentrations (p = 0.034). Twenty five percent of variation in INR could be explained by these variables (adjusted R2 = 0.25). Correlation analysis of data showed that warfarin dosage was significantly and negatively correlated with patient age (r = -0.42; p <0.0001). Patient age accounted for 25% of variation in warfarin dosage requirements (R2 = 0.25). The combined effects of age and vitamin K appear to account for much of the inter-individual variability in warfarin dosage requirements.

Adult↗