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At least 19 recordsLinked to original sources
PubMed1992

Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis.

BACKGROUND: In most countries, heparin is used in the initial treatment of patients with deep-vein thrombosis. Well-designed studies establishing the efficacy of heparin therapy are lacking, however. Treatment with acenocoumarol alone, according to the hypothesis that high dosages of oral anticoagulants obviate the need for heparin, is considered an effective alternative in some countries. METHODS: In a randomized, double-blind study we compared the efficacy and safety of continuous intravenous heparin plus acenocoumarol with the efficacy and safety of acenocoumarol alone in the initial treatment of outpatients with proximal-vein thrombosis. The principal study end point was a confirmed symptomatic extension or recurrence of venous thromboembolism during six months of follow-up. In addition, we assessed asymptomatic extension or pulmonary embolism by repeating venography and lung scanning after the first week of treatment. The incidence of major bleeding was determined during three months of follow-up. RESULTS: The study was terminated early by the Data Safety and Monitoring Committee because of an excess of symptomatic events in the group that received acenocoumarol alone (in 12 of 60 patients [20 percent], as compared with 4 of 60 patients [6.7 percent] in the combined-therapy group by intention-to-treat analysis; P = 0.058). Asymptomatic extension of venous thrombosis was observed in 39.6 percent of the patients in the acenocoumarol group and in 8.2 percent of patients treated with heparin plus acenocoumarol (P < 0.001). Major bleeding complications were infrequent and comparable in the two groups. CONCLUSIONS: Patients with proximal-vein thrombosis require initial treatment with full-dose heparin, which can safely be combined with acenocoumarol therapy.

Acenocoumarol↗
PubMedDate not supplied

Low-dose vitamin K1 versus short-term with holding of acenocoumarol in the treatment of excessive anticoagulation episodes induced by acenocoumarol. A retrospective comparative study.

BACKGROUND: No consensus exists about the management of iatrogenically induced excessive hypocoagulability episodes. OBJECTIVE: To compare the two most common therapeutic approaches in such situations (discontinuation of the oral anticoagulant vs. low-dose subcutaneous vitamin K1) when acenocoumarol is the normally used anticoagulant. PATIENTS AND METHODS: The study was retrospective and comparative. Patients received antithrombotic therapy using acenocoumarol. Anticoagulant plasmatic activity was assessed through the international normalized ratio (INR) recorded from December 1994 to December 1997 at two medical centers. RESULTS: INR is brought faster to a safe range in patients treated with low-dose vitamin K1 (p = 0.01). Their long-term behavior is also more stable and predictable and no resistance to the oral anticoagulant was found. CONCLUSION: Low-dose vitamin K1 is a safer therapeutic option compared to simply withholding the oral anticoagulant. Its best scheme of administration, however, has yet to be defined.

Acenocoumarol↗
PubMed2000

Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes.

The oral anticoagulant acenocoumarol is given as a racemic mixture. The (S)-enantiomer is rapidly cleared and is the reason why only (R)-acenocoumarol contributes to the pharmacological effect. The objective of the study was to establish the cytochrome P450 (CYP) enzymes catalyzing the hydroxylations of the acenocoumarol enantiomers. Of various cDNA-expressed human CYPs, only CYP2C9 hydroxylated (S)-acenocoumarol. Hydroxylation occurred at the 6-, 7-, and 8-position with equal K(m) values and a ratio of 0.9:1:0.1 for V(max). CYP2C9 also mediated the 6-, 7-, and 8-hydroxylations of (R)-acenocoumarol with K(m) values three to four times and V(max) values one-sixth times those of (S)-acenocoumarol. (R)-Acenocoumarol was also metabolized by CYP1A2 (6-hydroxylation) and CYP2C19 (6-, 7-, and 8-hydroxylation). In human liver microsomes one enzyme only catalyzed (S)-acenocoumarol hydroxylations with K(m) values < 1 microM. In most of the samples tested the 7-hydroxylation of (R)-acenocoumarol was also catalyzed by one enzyme only. The 6-hydroxylation was catalyzed by at least two enzymes. Sulfaphenazole could completely inhibit in a competitive way the hydroxylations of (S)-acenocoumarol and the 7-hydroxylation of (R)-acenocoumarol. The 6-hydroxylation of (R)-acenocoumarol could be partially inhibited by sulfaphenazole, 40 to 50%, and by furafylline, 20 to 30%. Significant mutual correlations were obtained between the hydroxylations of (S)-acenocoumarol, the 7-hydroxylation of (R)-acenocoumarol, the 7-hydroxylation of (S)-warfarin, and the methylhydroxylation of tolbutamide. The results demonstrate that (S)-acenocoumarol is hydroxylated by a single enzyme, namely CYP2C9. CYP2C9 is also the main enzyme in the 7-hydroxylation of (R)-acenocoumarol. Other enzymes involved in (R)-acenocoumarol hydroxylation reactions are CYP1A2 and CYP2C19. Drug interactions must be expected, particularly for drugs interfering with CYP2C9. Also, drugs interfering with CYP1A2 and CYP2C19 may potentiate acenocoumarol anticoagulant therapy.

Acenocoumarol↗
PubMed2004

The effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol.

OBJECTIVE: The potential for a drug interaction was investigated between nateglinide, an oral antidiabetic agent, and acenocoumarol, an oral anticoagulant, as these drugs are primarily metabolized via CYP2C9. METHODS: A two-period, randomized, double-blind, two-way crossover study design was employed to evaluate the effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol in 11 healthy male or female subjects. All subjects received either nateglinide 120 mg t.i.d. or placebo for 5 days in a crossover fashion and a single 10-mg dose of acenocoumarol on day 3. Plasma concentrations of R- and S-acenocoumarol and the anticoagulation parameters [prothrombin time (PT) and international normalized ratio of PT (PTINR)] were determined for 72 h following acenocoumarol administration. The pharmacokinetic and pharmacodynamic parameters of acenocoumarol were determined by noncompartmental analysis. RESULTS: The mean (coefficient of variation (CV%)) area under the concentration-time curve (AUC(0-t)) of R-acenocoumarol in the presence and absence of nateglinide was 4217 (23%) and 3831 (24%) ng.h/ml, respectively. The corresponding values for S-acenocoumarol were 397 (20%) and 382 (23%), respectively. The mean (CV%) C(max) of R-acenocoumarol in the presence and absence of nateglinide was 304 (16%) and 316 (16%), respectively and the corresponding values for S-acenocoumarol were 142 (36%) and 141 (34%), respectively. The 90% confidence intervals indicated that exposure parameters, AUC(0-t) and C(max), of both R- and S-acenocoumarol were within the acceptable limits of 0.8-1.25. The mean (CV%) of area under the concentration-time curve of PT (AUC(PT)) following acenocoumarol administration in the presence and absence of nateglinide was 1170 (10%) and 1136 (8%), respectively. The corresponding AUC(INR) values were 104 (13%) and 99 (10%), respectively. Nateglinide co-administration has no influence on the PT or PTINR of acenocoumarol (p > 0.05). CONCLUSION: Co-administration of nateglinide does not influence either the pharmacokinetics or the anticoagulant activity of R- and S-acenocoumarol in healthy subjects. This suggests that no dosage adjustments will be required when nateglinide and acenocoumarol are coadministered in clinical practice.

Acenocoumarol↗
PubMed2004

Pharmacokinetic drug-drug interaction of the novel anticancer agent E7070 and acenocoumarol.

E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700 mg/m2 given as a 1-h infusion. In vitro studies have shown that E7070 has the potential to inhibit several cytochrome P450 (CYP)-enzymes, including CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9. This study was performed to investigate the interaction between E7070 and acenocoumarol. Blood samples were obtained from two patients receiving daily oral maintenance treatment with acenocoumarol both prior to and following treatment with E7070. In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070. Pharmacokinetic parameters of acenocoumarol were calculated by noncompartmental analysis and revealed that in both patients the area under the concentration-time curve up to 24 h after the acenocoumarol administration was higher following E7070 (2.56 and 1.58 h*micromol/L) compared to the systemic exposure in the absence of E7070 (1.87 and 1.23 h*micromol/l). The formation of acenocoumarol metabolites was retarded by E7070 at already low concentrations (2.1 microM). The plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070 (259 microM). These results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic clearance. Displacement of acenocoumarol's plasma protein binding by E7070 may also occur but to a minor extent. In the absence of careful monitoring this drug-drug interaction may result in hypoprothrombinemia and a hemorrhagic tendency.

Acenocoumarol↗
PubMed2001

Altered pharmacokinetics of R- and S-acenocoumarol in a subject heterozygous for CYP2C9*3.

OBJECTIVE: Our objective was to study the pharmacokinetics of R - and S -acenocoumarol in a subject who was highly sensitive to the anticoagulant effect of acenocoumarol. The subject was found to be heterozygous for CYP2C9*3. METHODS: The plasma pharmacokinetics of the acenocoumarol enantiomers was established after an oral dose of 8 mg of racemic acenocoumarol. Urine was collected to establish the formation clearance of the 6- and 7-hydroxy metabolites of R - and S -acenocoumarol. RESULTS: The pharmacokinetics of S -acenocoumarol in this subject differed greatly (oral clearance, 6%-10%; half-life of elimination, 400%-500%) from the values of a [wt/wt] control and from population values. R -acenocoumarol clearance was at the lower level of population values. The apparent formation clearances of the metabolites were low-approximately 10% of control activity for the hydroxylations (6- and 7-) of S -acenocoumarol and for the 7-hydroxylation of R -acenocoumarol. The rate of the 6-hydroxylation of R -acenocoumarol was about 50% of control values. CONCLUSION: The presence of even one copy of CYP2C9*3 reduces profoundly the metabolic clearance of S -acenocoumarol. As a result the first-pass effect of elimination is abolished and the maintenance time is increased. S -Acenocoumarol, which is normally clinically inactive, will now exert main anticoagulant activity.

Acenocoumarol↗
PubMed1998

Warfarin or acenocoumarol: which is better in the management of oral anticoagulants?

Warfarin is employed more frequently than acenocoumarol because of its longer half-life (36 h), theoretically providing more stable anticoagulation, and avoiding factor VII fluctuations that potentially occur during acenocoumarol treatment (half-life 10 h). The aim of our study was to compare acenocoumarol with warfarin in the same group of 103 patients who started oral anticoagulation with acenocoumarol and then changed to warfarin. In these patients we compared the previous period of six months on acenocoumarol treatment (July-December 1996) with a new six-month period on warfarin (July-December 1997). We wished to know whether warfarin could improve the quality and the stability of oral anticoagulation of our patients and whether there was a difference between the two drugs in the weekly mean dose per patient. Moreover in order to detect the possible daily fluctuation of factor VII, we evaluated a further group of 54 patients. A subgroup of these patients was treated with warfarin while another received acenocoumarol. In the first group of patients, 1,158 and 1,064 PTs were carried out with acenocoumarol and warfarin, respectively. The percentage of PTs in the therapeutic range was 59% with acenocoumarol and 62% with warfarin (p=0.4). The mean number of visits per patient was 12 and 11, and the mean number of visits in the therapeutic range was 7 and 7, respectively. The last check in file method did not show any difference between the two drugs. Overdose states were 51 (4.4%) with acenocoumarol and 30 (2.8%) with warfarin (p=0.4). A good correlation (r=0.92) was found between the acenocoumarol and the warfarin weekly mean dose. The mean warfarin/acenocoumarol weekly dose ratio was 2.08 (range: 1.25-3.30; CI 95%: 1.99-2.16). In the second group of patients, factor VII levels with both drugs were higher 24 h after administration than 16 h after, showing that their daily fluctuation was independent of the drug's half-life, since factor VII levels in patients with a low vitamin K intake were not increased. Our results showed that warfarin did not appear to be better than acenocoumarol in the performance of an Anticoagulation Clinic in terms of PTs within the therapeutic range per patient. It seems that the behaviour of factor VII was affected by the intake of vitamin K rather than by the short half-life of acenocoumarol.

Acenocoumarol↗
PubMed2003

Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype.

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 2C9 is one of the major CYP enzymes involved in the biotransformation of drugs, among others, the oral anticoagulant acenocoumarol. The enzyme has several polymorphisms, with the CYP2C9*2 and CYP2C9*3 variants most commonly present in white patients. Patients with the CYP2C9*3 variant are known to require a lower maintenance dose of racemic acenocoumarol. We investigated the impact of the polymorphisms CYP2C9*2 and CYP2C9*3 on the pharmacokinetics of R- and S-acenocoumarol. METHODS AND RESULTS: In the first study 26 healthy volunteers with the genotype *1/*1 (n = 9), *1/*2 (n = 7), *1/*3 (n = 6), *2/*3 (n = 3), and *2/*2 (n = 1) were given 8 mg of racemic acenocoumarol as a single oral dose. Plasma R- and S-acenocoumarol concentrations were assayed at 4, 7, and 24 hours. Mean plasma S-acenocoumarol concentrations at 7 hours were higher in subjects with a variant allele; the differences were significant (P =.01) for the *1/*3 and *2/*3 genotypes. In the second study, the oral pharmacokinetics of acenocoumarol was investigated in 6 subjects (*1/*1 [n = 3] and *1/*3 [n = 3]). The mean oral clearance of S-acenocoumarol was 45% lower in the CYP2C9*1/*3 genotypes (10.9 +/- 3.0 L/h versus 19.8 +/- 3.1 L/h, P =.02). Plasma half-life was prolonged from 1.0 +/- 0.2 hours to 2.0 +/- 0.7 hours (P =.09). R-acenocoumarol pharmacokinetics did not differ between the genotypes. There was no difference in mean international normalized ratio at 24 hours, which was 1.2 in both groups. In vitro enzyme kinetics showed reduced (85%) intrinsic activity of the *3 enzyme to catalyze the hydroxylations of S-acenocoumarol. The lower activity resulted from higher Michaelis-Menten constant (2-fold) and lower maximum rate of metabolism by an enzyme-mediated reaction (by 70%). The activity of the *2 enzyme was 50% of the wild-type one. CONCLUSION: The results show S-acenocoumarol pharmacokinetics to be dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs oral clearance of the coumarin.

Acenocoumarol↗
PubMed1993

Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics.

1. To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2. The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6- and 7-position (accounting for 63 to 99% of the metabolic clearances). 3. Due to the lower Km values of R- and S-acenocoumarol and higher Vmax values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4. The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol. 5. Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P < 0.025), the 6- and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6. Sulphaphenazole competitively inhibits the 7- and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R- and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 microM). 7. Omeprazole partly (40-80%) inhibits the 6- and 7-hydroxylation of R-warfarin (Ki = 99 and 117 microM) and of R- (Ki = 219 and 7.2 microM) and S-acenocoumarol (Ki = 6.1 and 7.7 microM) but not S-warfarin in a competitive manner. 8. Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine.9. The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7- and 6-hydroxylase).

Acenocoumarol↗
PubMedDate not supplied

Phenylbutazone-hydroxycoumarol interactions. Effects on steady state disposition, hepatocellular distribution, and biliary excretion of (S)-acenocoumarol in rats.

The effect of phenylbutazone on the disposition of (S)-acenocoumarol in the rat was studied at steady state conditions of distribution and elimination. (S)-Acenocoumarol was administered by constant rate infusions (1 microgram/min). The biliary excretion of 6- and 7-hydroxylated acenocoumarol was followed and the intrahepatic distribution was investigated. Phenylbutazone (50 mg/kg) increased the plasma unbound fraction about 4-fold. (S)-Acenocoumarol plasma clearance was enhanced (2.8 +/- 0.15 vs. 1.54 +/- 0.14 ml/min) but the unbound plasma clearance was reduced by 50% (67 +/- 9 vs. 140 +/- 27 ml/min). Phenylbutazone caused an intrahepatic redistribution of (S)-acenocoumarol, i.e. the drug shifted from the cytosol to the 10,000g pellet. The cytosolic unbound concentration, however, was increased. The (S)-acenocoumarol content in the microsomal fraction was not affected. The biliary excretion rate of total metabolite (free plus conjugated) comprised 50% of the (S)-acenocoumarol infusion rate in controls and was slightly stimulated (+20%) by phenylbutazone. The biliary excretion of free metabolites, however, was greatly increased (62 +/- 7 vs. 22 +/- 6 ng/min for 6-hydroxy-acenocoumarol; 337 +/- 38 vs. 141 +/- 32 ng/min for 7-hydroxy-acenocoumarol). This effect is probably due to stimulation of a hepatic biliary transport system; the rate constant for transport of 7-hydroxy-acenocoumarol was enhanced 5-fold (0.107 +/- 0.03 vs. 0.021 +/- 0.007 min-1).

Acenocoumarol↗
PubMed2004

Aging and oral anticoagulant therapy using acenocoumarol.

We evaluated the influence of aging, gender and indications of anticoagulant therapy on acenocoumarol requirements in 1845 patients from 30 to 99 years old receiving acenocoumarol therapy who were monitored in our hospital outpatient anticoagulation clinic from March 1993 through September 1999. The patients were stratified in seven age groups, comprising older than 80 years and the five decades between 30 years and 80 years. We found a progressive decrease in the acenocoumarol requirements from 30 years to 80 years (rho=-0.98), which was estimated as 2.7 mg/week per decade (11.5% per decade). This decrease was not the consequence of a different range of anticoagulation or differences in body weight. We did not find correlation between the decrease of acenocoumarol requirements and different biochemical parameters including, creatinine, calcium and alanine aminotransferase. We detected a progressive decrease in levels of serum total proteins but changes in this parameter did not correlate with the amount of acenocoumarol requirements. The dose of acenocoumarol (mg/week per patient) of those patients suffering from venous thromboembolism were higher than the remainder of the patients (18.4 +/- 9.3 versus 14.5 +/- 7.8, P <0.0001). This finding was also detected, after stratifying the patients by decades, from 60 years to 80 years. In conclusion, requirements of acenocoumarol decrease with aging; this decrease represents an important amount from 30 years to 80 years and it should be kept in mind to choose the initial dose of acenocoumarol. Patients with venous thromboembolism required a higher dose of acenocoumarol.

Acenocoumarol↗
PubMed1984

The potentiation of acenocoumarol anticoagulant effect by amiodarone.

Out of 690 patients (337 males and 353 females) on long-term acenocoumarol therapy, 80 (35 males and 45 females) were taking amiodarone. Forty patients had started amiodarone treatment while being treated with acenocoumarol. Of these, nine patients had begun amiodarone treatment while taking acenocoumarol. The relation between the daily dose of acenocoumarol and the prothrombin ratio (AC dose/PR ratio) has been considered a useful indicator to study the interaction between amiodarone and acenocoumarol. Differences of acenocoumarol daily dose between takers and non-takers of amiodarone were statistically significant (t = 5.35; P less than 0.001) for the whole population, for all the age groups, and also among males (t = 2.43; P less than 0.01) as well as among females (t = 5.38; P less than 0.001). Out of 40 patients chronically treated with acenocoumarol in whom amiodarone was instituted, 32 showed a decrease of the AC dose/PR ratio, while in eight patients no change was recorded (paired t-test, t = 5.82; P less than 0.001). In 15 patients who were being concomitantly treated with acenocoumarol and amiodarone, amiodarone was discontinued. An increase of the AC dose/PR ratio was recorded (paired t-test, t = 4.01; P less than 0.001). Nine patients had started treatment with amiodarone while receiving acenocoumarol and a decrease of the AC dose/PR ratio was documented; amiodarone was discontinued some months later, and an increase of the AC dose/PR ratio was seen.

Acenocoumarol↗
PubMed2004

Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype.

NSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, however a pharmacokinetic mechanism resulting in an increased International Normalised Ratio (INR) was proposed in some case reports in warfarin treated patients. In this retrospective cohort study the influence of diclofenac, naproxen and ibuprofen on the INR of outpatients stabilised on acenocoumarol therapy was investigated. We also determined the role of cytochrome P450 2C9 (CYP2C9) polymorphism on coumarin dosage and INR in NSAID users. The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed. Patients whose INR rose above the upper level of the therapeutic range (INR above 3.5 or 4.0) after an NSAID under study was added to the acenocoumarol therapy, were compared with patients who did not show such an elevation. A two-sample t-test (average acenocoumarol dosage, age), and chi-square tests (sex, therapeutic range, type of NSAID) were used to test for differences. Genotyping was carried out by analysing blood samples for the relevant CYP2C9 alleles. The study population consisted of 112 patients on stable acenocoumarol therapy, of which 52 (46%) showed an elevation of the INR above the desired therapeutic level (INR 3.5 and 4.0 respectively) after the start of an NSAID under study. In 12 patients, the INR increased above 6. The INR of the other 60 patients (54%) remained constant after the start of one of the NSAIDs under study. There were no statistically significant differences between patients with increased INR and patients without increased INR with regard to age, sex, therapeutic range and average acenocoumarol dosage. Eighty patients, of whom 36 showed an increased INR as a result of a potential acenocoumarol-NSAID drug interaction, were included in the genotyping study. No association between CYP2C9 genotype and an increased INR as a result of the drug-drug interaction was found. In nearly half of a cohort of elderly patients, the INR increased beyond the therapeutic range (INR 3.5 or 4.0) as a result of a potential pharmacokinetic drug-drug interaction between acenocoumarol and diclofenac, naproxen and ibuprofen. The average increase in INR was between 1 and 4. Polymorphism of CYP2C9 does not seem to be a relevant risk factor for the NSAID-acenocoumarol interaction.

Acenocoumarol↗
PubMed1999

No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics.

OBJECTIVE: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. METHODS: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). RESULTS: The median (range) areas under the concentration-time curve (AUC) for (R)-acenocoumarol were 3458 (3035-7312) microg x h 1(-1) in the absence of and 3667 (2907-7741) microg x h 1(-1) in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381-853) microg x h 1(-1) and 612 (425-1241) microg x h 1(-1). The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. CONCLUSION: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics.

Acenocoumarol↗
PubMed1996

Stereoselective interaction between piroxicam and acenocoumarol.

1. An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers. 2. Eight healthy male volunteers received an oral dose of 4 mg rac-acenocoumarol on days 1 and 8, plus 40 mg piroxicam orally 2 h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24 h interval. 3. The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: Cmax+28.0% (s.d.23.8), P < 0.05; AUC(0, 24 h)+47.2% (21.5), P < 0.005; and t1/2 +38.0% (34.5), P < 0.01. A concomitant decrease of CL/F was observed: -30.8% (10.0), P < 0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: Cmax: +9.5% (s.d.36.6), AUC(0, 24 h): + 15.4% (23.4), t1/2: +19.9% (42.0), and CL/F: -9.8% (20.5). V/F remained unchanged for both enantiomers. 4. Piroxicam plasma AUC(0, 24 h) correlated closely with R- and S-acenocoumarol AUCs on day 1 (r = 0.901, P < 0.005 and r = 0.797, P < 0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol (r = 0.903, P < 0.001) and S-acenocoumarol (r = 0.711, P < 0.05). 5. Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.

Acenocoumarol↗
PubMed2002

Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol.

The 2C9*3 and 2C9*2 polymorphisms of cytochrome P-450 CYP2C9 are associated with hypersensitivity to warfarin and bleeding. The effect of these polymorphisms on sensitivity to acenocoumarol is unknown. Three groups of patients, with low, medium, or high acenocoumarol-dose requirements, were studied. Age influenced the acenocoumarol sensitivity. Bearing the 2C9*3 allele was associated with the need for a lower acenocoumarol dose (odds ratio [OR], 6.02; 95% confidence interval [CI], 1.50-24.18); 80% of carriers of the 2C9*3 allele required a low dose. The 2C9*2 allele was associated with a lower acenocoumarol-dose requirement (OR, 2.70; 95% CI, 1.11-6.58) because of a reduced risk of the need for a high acenocoumarol dose (4.8% of the patients in the high-dose group carried the 2C9*2 allele versus 34.1% and 30.2%, respectively, in the medium-dose and low-dose groups). Therefore, carriers of 2C9*3 may need a low initial loading dose of acenocoumarol. Because acenocoumarol sensitivity with the 2C9*2 variant does not seem to be clinically relevant, the drug could be an alternative to warfarin in 2C9*2 carriers.

Acenocoumarol↗
PubMed2005

[Significance of cytochrome P450 2C9 genotype for the bleeding complications in patients treated with acenocoumarol].

INTRODUCTION: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the comorbidity, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. AIM: The influence of CYP2C9 polymorphism on the effectiveness of the--in Hungary for oral anticoagulation exclusively used--acenocoumarol therapy and on the occurrence of bleeding complications was investigated. METHODS: Genotyping of 421 patients including 183 men and 238 women, (mean age 66.2 +/- 11.8 years) who took acenocoumarol (Syncumar) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. RESULTS: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p < 0.001) lower than in patients with the wild type allele (2.12 +/- 0.96 mg/day and 2.90 +/- 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p < 0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnesis was significantly (p < 0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. CONCLUSIONS: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

Acenocoumarol↗
PubMed1990

Detection of drug interactions with single dose acenocoumarol: new screening method?

In this study, a design for the evaluation of drug interactions with an oral anticoagulant drug was investigated. The interaction between a single dose of acenocoumarol and cimetidine or pentobarbitone was studied. Nine healthy volunteers received three treatments: 1) 10 mg acenocoumarol in combination with cimetidine, 2) 10 mg acenocoumarol in combination with placebo, 3) 10 mg acenocoumarol after one week pretreatment with pentobarbitone. The pharmacokinetics and the pharmacodynamics of acenocoumarol were monitored for 36 h. In all subjects the plasma concentration of acenocoumarol remained consistently higher during cimetidine treatment and consistently lower after pentobarbitone pretreatment compared to placebo treatment. Cimetidine increased the anticoagulant response of acenocoumarol as measured by the Thrombotest and pentobarbitone decreased this response in all subjects. It is concluded from this study that both pharmacokinetic and pharmacodynamic drug interactions with acenocoumarol (and presumably other oral anticoagulants) can be detected after single doses, possibly obviating the use of long-term anticoagulation in healthy volunteers.

Acenocoumarol↗