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PubMed1982

Lack of effect of cimetidine on action of phenprocoumon.

In patients on oral warfarin, nicoumalone and phenindione an increase in the anticoagulant effect has been described during concomitant treatment with cimetidine. Therefore the effect of cimetidine on the steady state dynamics of phenprocoumon has been investigated in ten outpatients. No change in the anticoagulant effect of phenprocoumon was observed during or after two weeks on cimetidine, as measured by the thrombotest coagulation method, prothrombin time, fibrinopeptide A concentration and plasma phenprocoumon level. The data show that cimetidine does not interact with the metabolism of phenprocoumon in contrast to warfarin. Thus, phenprocoumon maintenance therapy when combined with concomitant cimetidine treatment can be considered not to carry an increased risk of haemorrhagic complications.

4-Hydroxycoumarins↗
PubMed1977

Interaction of allopurinol with phenprocoumon in man.

Conditions in two patients on long-term phenprocoumon (Marcumar) treatment are reported who had signs of phenprocoumon overdosage when given simultaneously allopurinol. The determination of phenprocoumon plasma concentrations in one patient showed that phenprocoumon accumulates for several weeks during treatment with allopurinol. Signs of phenprocoumon overdisage thus can appear long time after starting allopurinol treatment.

4-Hydroxycoumarins↗
PubMed2006

Obesity is associated with a slower response to initial phenprocoumon therapy whereas CYP2C9 genotypes are not.

BACKGROUND: Initiation of phenprocoumon therapy is associated with a variable individual response. The CYP2C9 genotype has been shown to influence the response to warfarin therapy, but such an effect on phenprocoumon therapy remains uncertain. METHOD: Two hundred sixty hospital patients started on phenprocoumon were recruited for this study. Body mass index (BMI), waist and hip circumference, dietary habits, comorbidity, and comedication were initially assessed. A 5' exonuclease assay (TaqManR) was used to analyze the presence of five polymorphisms of the CYP2C9 gene in each of the study patients. Study endpoints included the time necessary to achieve the international normalized ratio (INR) target (INR >2) and the total drug amount required to attain target INR. For 250 of 260 patients, the subsequent required daily maintenance dose of phenprocoumon was also recorded. RESULTS: Both the necessary time and total dose required to attain target INR correlated significantly with BMI. The leaner the patient, the shorter the required time interval [BMI <22 (n=31), 5.48+/-2.49 days; BMI 22-25 (n=70), 6.09+/-2.40; BMI 25-30 (n=113), 6.76+/-3.61; BMI >30 (n=46), 8.50+/-5.75; p=0.001] and the lower the required dosage until the therapeutic range was achieved [BMI <22 (n=31), 23.8+/-12.1 mg; BMI 22-25 (n=70), 25.9+/-11.4 mg; BMI 25-30 (n=113), 29.6+/-25.2; BMI >30 (n=46), 35.8+/-19.7; p=0.027]. Overweight and waist circumference as a surrogate marker for abdominal fat were also associated significantly with these two parameters. Moreover, obesity was associated with a lower body-weight-adjusted maintenance dosage. All CYP2C9 genotypes that were tested failed to reveal an association with individual response variability. CONCLUSION: Patient obesity appears to directly correspond to the amount of phenprocoumon required during initiation of therapy. The CYP2C9 genotype was not shown to influence the necessary therapeutic dosage.

Aged↗
PubMed2004

Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status.

OBJECTIVE: Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial phase of phenprocoumon treatment. METHODS: A prospective follow-up study was performed at 2 anticoagulation clinics in The Netherlands. Included subjects started phenprocoumon during the study period, had their first check of the international normalized ratio (INR) on the third or fourth day of therapy, and had an indication for the low therapeutic range (INR, 2.0-3.5). CYP2C9 genotypes ( CYP2C9*1 , CYP2C9*2 , and CYP2C9*3 ) were assessed, and data on indication, INR checks, comedication, and comorbidity were collected. RESULTS: After genotyping, 284 subjects were available for analysis. Of these, 186 (65.5%) were homozygous carriers of the CYP2C9 wild-type allele ( CYP2C9*1/*1 ), 61 (21.5%) were carriers of the CYP2C9*2 allele, and 37 (13.0%) were carriers of the CYP2C9*3 allele. Compared with homozygous CYP2C9*1/*1 subjects, carriers of CYP2C9*2 or *3 had an increased risk of severe overanticoagulation (INR >6.0). The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 3.09 (95% confidence interval [CI], 1.56 to 6.13; P=.001), and the hazard ratio for CYP2C9*3 versus CYP2C9*1/*1 was 2.40 (95% CI, 1.03 to 5.57; P=.042). Carriers of CYP2C9*2 also had a lower chance to achieve stability in the follow-up period. The hazard ratio for CYP2C9*2 versus CYP2C9*1/*1 was 0.61 (95% CI, 0.43 to 0.85; P=.003). Carriers of the CYP2C9*2 or *3 allele needed a significantly lower phenprocoumon dosage compared with homozygous CYP2C9*1/*1 subjects. CONCLUSION: The presence of at least 1 CYP2C9*2 or *3 allele in phenprocoumon users is associated with an increased risk of severe overanticoagulation. Similar to warfarin and acenocoumarol, phenprocoumon had a lower dosage requirement in carriers of CYP2C9*2 or *3 compared with that in CYP2C9 wild-type subjects.

Aged↗
PubMed1982

Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon.

To compare the marked hypoprothrombinemic augmentation in man of racemic warfarin sodium by the pyrazolons phenylbutazone and sulfinpyrazone with that of the coumarin anticoagulant phenprocoumon, these interactions were studied prospectively in six normal subjects. Large single doses of racemic phenprocoumon, 0.6 mg/kg orally, were administered with and without daily phenylbutazone, 300 mg, or sulfinpyrazone, 400 mg, beginning three days before phenprocoumon and continuing for 14 days. Daily blood samples were drawn for phenprocoumon content and one-stage prothrombin time. Phenylbutazone markedly increased both the phenprocoumon concentrations and prothrombin times, whereas sulfinpyrazone did not.

4-Hydroxycoumarins↗
PubMed1990

The effects of frusemide and probenecid on the pharmacokinetics of phenprocoumon.

We have studied the pharmacokinetics of phenprocoumon with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg b.i.d. for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg q.i.d. for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in AUC from 295 to 157 micrograms.h.ml-1, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucuronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites.

Administration, Oral↗
PubMed1993

Variation in the binding affinity of warfarin and phenprocoumon to human serum albumin in relation to surgery.

The binding equilibria of warfarin and phenprocoumon with defatted human serum albumin were studied by equilibrium dialysis in 33 mM sodium phosphate buffer, pH 7.4, 37 degrees C. The binding isotherms for both ligands were consistent with binding to two similar and independent sites in the albumin molecule. The binding affinity of warfarin was markedly increased on adding palmitic acid up to palmitate 4 mol per mol albumin and then it decreased. The binding affinity of phenprocoumon varied similarly but to a lesser degree. Serum samples were obtained from 14 patients undergoing knee joint surgery, six consecutive samples from each patient. The binding affinity of warfarin and phenprocoumon added in low concentrations to the serum samples was consistently less than to purified albumin. The binding affinity for warfarin increased slightly with increasing fatty acid concentrations during surgery, but the increase was much less than expected from the in vitro studies. The binding of phenprocoumon in the serum samples was not influenced by changing fatty acid concentration. The binding affinity for both drugs decreased markedly during the three days following surgery.

Aged↗
PubMed1976

Pharmacokinetics of phenprocoumon in man investigated using a gas chromatographic method of drug analysis.

A gas chromatographic method for the determination of phenprocoumon (Marcumar) in serum and urine is described, which facilitates accurate values down to 0.5 mug phenprocoumon/ml serum. After the i.v. administration of 20 mg phenprocoumon in a single dose to 4 healthy volunteers the following pharmacokinetic data were obtained: After the initial fast decrease (phase 1) of the serum level of phenprocoumon, probably due to the distribution into the different compartments is followed by a subsequent slower fall (phase 2) which occurs with a serum half-life of 157 h. The apparent distribution volume was 6.51. Analysis of the urine demonstrated that 90% of the excreted phenprocoumon detected was in the glucuronide form.

Chromatography, Gas↗
PubMed2005

Stereospecific pharmacokinetic characterisation of phenprocoumon metabolites, and mass-spectrometric identification of two novel metabolites in human plasma and liver microsomes.

Phenprocoumon belongs to the group of vitamin K antagonists (VKAs), for example warfarin and acenocoumarol. It is widely used for therapeutic anticoagulation and clinically administered as a racemate. Both enantiomers are partially metabolized by the polymorphic CYP2C9 enzyme. The pharmacokinetics are, however, substantially less dependent on CYP2C9 activity or genotype than for other CYP2C9-metabolised VKAs, and pharmacokinetic differences for the enantiomers are only minor. We have investigated the stereospecific pharmacokinetics of the monohydroxylated phenprocoumon metabolites in human plasma by achiral-chiral LC-LC-MS-MS coupling. In addition to the known metabolites, 4'-, 6-, and 7-hydroxyphenprocoumon, two other monohydroxylated metabolites (M1 and M2) were detected in plasma and human liver microsomal incubations. One of these was identified as 2'-hydroxyphenprocoumon by comparison with synthetic standards; the other seemed to be a side-chain-hydroxylated derivative. Analysis of enantiomeric metabolite ratios after a single oral dose of phenprocoumon revealed changes over time with an overall preponderance of the respective (R) enantiomers. The minor role of CYP2C9 in 4'-hydroxy-PPC formation and the effect of CYP2C9 genotype for (S)-6- and (S)-7-hydroxy-PPC were confirmed. M1 and M2 are formed highly stereoselectively, without dependence on CYP2C9 genotype. These may be interpreted as alternative metabolic pathways that render phenprocoumon less dependent on CYP2C9 activity or genotype.

Anticoagulants↗
PubMed2002

No clinically relevant drug interaction between paracetamol and phenprocoumon based on a pharmacoepidemiological cohort study in medical inpatients.

OBJECTIVE: A recent case control study suggests that paracetamol at a dosage above 1300 mg/day increases the anticoagulant effects of warfarin. In many European countries, phenprocoumon and not warfarin is used as an anticoagulant. However, the effects of paracetamol on the anticoagulant effects of phenprocoumon have so far not been evaluated. METHODS: This study is based on the data recorded prospectively between 1996 and 1998 in two Swiss teaching hospitals in the pharmacoepidemiological database of the SAS/CHDM project. As a first step, all phenprocoumon-treated patients with at least one international normalized ratio (INR) determination at least 4 days after cohort entry were selected and evaluated concerning paracetamol co-administration. The "paracetamol group" included only patients receiving at least 1300 mg/day paracetamol on the 3 days preceding the INR determination, whereas the comparison group contained only patients without paracetamol exposure during hospital stay. Thereafter, INR values of the paracetamol and the comparison groups were compared. RESULTS: The paracetamol and the comparison groups included 54 and 180 patients, respectively. Patients' characteristics in both groups were comparable. Patients in the paracetamol group received on average 2220 +/- 651 mg/day paracetamol. The median duration of paracetamol exposure was 5 days. The median difference in INR values between the paracetamol and the comparison groups was -0.3 (with a 99% confidence interval of -0.6, 0.1). CONCLUSIONS: These results suggest that paracetamol co-administration at a dosage of 2000-2500 mg/day for 3 days has no clinically relevant effects on the anticoagulant effects of phenprocoumon.

Acetaminophen↗
PubMed2003

Determination of bleeding risk using genetic markers in patients taking phenprocoumon.

BACKGROUND: In patients on oral anticoagulation with warfarin, genetic variations of the cytochrome P 450-CYP2C9 have recently been associated with very low warfarin requirements. Patients needing low doses had an increased risk for bleeding complications. In Germany, phenprocoumon (having a similar metabolic pathway) is the most commonly employed vitamin K antagonist. Treatment is usually monitored by general practitioners (GPs). OBJECTIVES: To determine whether CYP2C9 variant alleles can serve as risk markers in general-practice patients anticoagulated with phenprocoumon. METHODS: All adult anticoagulated patients in 12 teaching general practices and one university outpatient clinic were to be recruited. Blood samples were taken from 185 patients during routine anticoagulation controls and tested for CYP2C9 mutations. Subjects answered a questionnaire concerning bleeding complications, drug intolerance, and personal and family medical history. Phenprocoumon dosages required for stable anticoagulation were recorded. Odds ratios (OR) with 95% confidence intervals (CI) were calculated based on 2-way cross-tabulations and multivariate logistic regression models, t-tests used where appropriate. RESULTS: Bleeding was reported by 19% of the patients, 2.2% of whom had suffered life-threatening bleeding. CYP2C9 variants were carried by 26.3% of 179 patients tested (17.9% *1/*2, 7.8% *1/*3, 0.6% *2/*3). While presence of a *2 allele was not associated with an increased risk (OR 0.35, CI 0.10-1.24), carriers of the rare *3 alleles had a higher risk of bleeding (OR 3.10, CI 1.02-9.40). With regard to bleeding, carrying CYP2C9*3 was highly specific (94%), though sensitivity was low at 17%; post-test probability of bleeding was 40%. CONCLUSIONS: CYP2C9*3 variants are associated with an increased bleeding risk in patients anticoagulated with phenprocoumon. Screening can identify patients with a high risk of bleeding. Appropriate clinical consequences (restricted indication for anticoagulation, careful induction, adjustment of target INR, closer monitoring or self-testing of INR) as well as the cost-effectiveness of screening for variant CYP2C9 with regard to patient outcomes should be subject of further research.

Aged↗
PubMed1978

The effect of bezafibrate on the fibrinolytic enzyme system and the drug interaction with racemic phenprocoumon.

The influence of a new hypolipidaemic agent, bezafibrate, on anticoagulant requirements and fibrinolysis was studied in 15 patients with hyperlipidaemia on long-term treatment with racemic phenprocoumon. Our results suggest a dose-dependent augmentation of the anticoagulant response to the coumarin drug. Treatment with bezafibrate at 450 and 600 mg daily required a reduction of the phenprocoumon dose by 18.5 and 33.5%, respectively. Correspondingly, the serum level of phenprocoumon decreased by 11.6 and 35.3%. No evidence for an altered drug elimination of racemic phenprocoumon could be found during treatment with bezafibrate. The results support the hypothesis that bezafibrate and analogous hypolipidaemic drugs enhance the response to oral anticoagulant drugs by increasing the affinity of the receptor site for coumarins or the rate of degradation of the vitamin-K-dependent clotting factors. The investigation of the fibrinolytic enzyme system demonstrated an increase of the fibrinolytic activity by enhancing the activity of the plasminogen activator. The lysis time for euglobulin clot was reduced significantly, plasma fibrinogen only moderately. The antiplasmin activity could not be altered substantially by a decrease of alpha1-antitrypsin and a slight increase of alpha2-macroglobulin. In contrast with the inhibition of platelet function the effect of bezafibrate on the fibrinolytic enzyme system showed no dose dependence.

4-Hydroxycoumarins↗
PubMed1994

High-affinity binding of two molecules of warfarin and phenprocoumon to human serum albumin.

Binding equilibria of warfarin, 3-(alpha-acetonylbenzyl)-4-hydroxycoumarin, and phenprocoumon, 3-(alpha-ethylbenzyl)-4-hydroxycoumarin, to defatted human serum albumin (Kabi Vitrum) were studied by equilibrium dialysis in a 33 mM sodium phosphate buffer (pH 7.4) at 37 degrees C. The binding data were analysed in terms of several acceptable sets of binding constants using a computerized curve fitting procedure. The findings were consistent with binding of two warfarin or two phenprocoumon molecules with high affinity and additional molecules bound with lower affinity. The binding of warfarin or phenprocoumon was explained by a model with two independent and equal high-affinity binding sites besides several independent weak sites in the albumin molecule (p < 0.01, by F-test). The findings were not consistent with binding of warfarin or phenprocoumon to a single high-affinity site besides several weak sites. A model of sequential binding of several ligand molecules to one locus is proposed.

Binding Sites↗
PubMed2004

Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure.

BACKGROUND/AIMS: Except for bleeding complications, other serious adverse reactions of coumarin anticoagulants such as hepatotoxicity or skin necrosis are comparatively rare. Nonetheless, a small number of coumarin-induced (sub-) acute liver failures has been published. METHODS: A retrospective analysis was performed of patients treated for liver disease between 1992 and 2002 at our department to evaluate the incidence, clinical findings and histopathology of coumarin-induced hepatotoxicity. RESULTS: The retrospective analysis revealed eight cases of phenprocoumon-induced hepatotoxicity, including three cases of (sub-) acute liver failure which resulted in two orthotopic liver transplantations and one fatal outcome. Five patients with phenprocoumon-induced hepatitis recovered well after anticoagulation was switched to another coumarin derivate or subcutaneous low molecular weight heparin. In all patients liver injury was predominantly of an hepatitic type. In the cases of (sub-) acute liver failure massive confluent liver cell necroses were histologically present, whereas among patients without liver failure mild portal to moderate active lobular hepatitis were observed. A retrospective analysis by BfArM (German Federal Institute for Drugs and Medical Devices) revealed 4390 cases of possible phenprocoumon-related adverse reactions since 1990, 2% of which had presented with hepatitis and 0.2% with liver failure. CONCLUSIONS: Phenprocoumon-induced liver disease is an uncommon complication, which can, however, cause (sub-) acute liver failure.

Acute Disease↗
PubMed2000

Evaluation of a simple dosage scheme for transition from phenprocoumon to warfarin in oral anticoagulation.

Phenprocoumon, whose elimination half-time is 144 hours, has been the traditional oral anticoagulant of choice in Europe. However, today's most widely used drug is warfarin, whose elimination half-time is 40 hours. This study aims to evaluate a method for safe transition from phenprocoumon to warfarin, which is sometimes required. Hence, the large difference in their elimination rates may on occasion lead to serious overdosage upon transition from one drug to the other. According to average equipotent doses, a stepwise increase in warfarin dose was calculated based on the elimination half-times of the two drugs. The dosage scheme was subsequently tested in a pilot study including 35 patients. The conversion scheme was then adjusted based on the results from the pilot study. The new scheme was tested in 69 patients. The transition factor was 2.3, which implies that equipotency was achieved when the warfarin dose was 2.3 times larger than the phenprocoumon dose (in mg). This scheme proved optimal for 75% of the patients. However, the dose had to be adjusted individually in the remaining 25% of the patients to a level corresponding to the measured international normalised ratios. No patients experienced haemorrhages or thromboembolic complications during the period of changeover. In conclusion, the proposed scheme for changing medication from phenprocoumon to warfarin is safe and convenient.

Administration, Oral↗
PubMed2000

Sensitive stereospecific determination of acenocoumarol and phenprocoumon in plasma by high-performance liquid chromatography.

We describe a normal-phase HPLC method for the stereospecific determination of R- and S-acenocoumarol and R- and S-phenprocoumon with S-warfarin as internal standard. The compounds were separated using a Whelk-O1 chiral stationary phase, detected by UV at 310 nm and quantified in the internal standard mode. Linearity was verified for acenocoumarol in the range of 15-2000 microg/l and for phenprocoumon from 15 to 2200 microg/l, respectively. The detection limits were 5 microg/l for all compounds. The recovery was >84% for R- and S-acenocoumarol and >74% for R- and S-phenprocoumon. The imprecision (C.V.) (50-1800 microg/l) for R- and S-acenocoumarol was <4.7% within-day and <7.8% between-day. For R- and S-phenprocoumon the respective values were <5.6% and <5.9%. The accuracy for all compounds was 96.5-110%.

Acenocoumarol↗
PubMed1979

A specific and sensitive method for the determination of the anticoagulant phenprocoumon in plasma.

A specific thin-layer chromatographic assay for phenprocoumon has been developed with a sensitivity of 5 ng/ml of plasma, using only 0.2 ml. This sensitivity is more than 20 times higher than that of the published methods. The drug is extracted from acidified plasma, an aliquot of the extract is applied to a silica-gel thin-layer plate and separated from interfering substances. The quantity of phenprocoumon is determined by fluorescence densitometry in situ. The standard deviation of the whole procedure is less than +/- 3%. The new procedure permits pharmacokinetic studies with low doses of phenprocoumon to be performed on volunteers. Furthermore, due to the high sensitivity of the method, it is possible to determine the free drug fraction of this highly protein-bound substance in the plasma of patients. It was shown that, in the therapeutic concentration range, phenprocoumon is bound by about 99.5% to the plasma proteins. Since the assay is simple and quick to perform, a large series of plasma samples can be analysed without any problems.

4-Hydroxycoumarins↗
PubMed1990

Analysis of phenprocoumon and its hydroxylated and conjugated metabolites in human urine by high-performance liquid chromatography after solid-phase extraction.

The anticoagulant phenprocoumon is mainly metabolized in humans to hydroxylated metabolites and their glucuronides. A method is described for the determination of phenprocoumon, 4'-hydroxyphenprocoumon, 6-hydroxyphenprocoumon, 7-hydroxyphenprocoumon, and their glucuronide and sulphate conjugates in human urine. Reversed-phase high-performance liquid chromatography is performed after selective extraction with disposable quaternary amine columns of untreated, and beta-glucuronidase- or sulphatase-treated urine samples. Urinary excretion data are presented for total, glucuronidated, sulphated and free phenprocoumon, 4'-hydroxyphenprocoumon, 6-hydroxyphenprocoumon and 7-hydroxyphenprocoumon in twelve patients after an average daily dosage of 1.3-4.2 mg phenprocoumon.

Adult↗