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PubMed1977

Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine.

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenouse dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5- to 2-fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest that phenprocoumon undergoes extensive enterohepatic recycling in man which can be effectively interrupted by cholestyramine.

4-Hydroxycoumarins↗
PubMed1999

Structural forms of phenprocoumon and warfarin that are metabolized at the active site of CYP2C9.

Possible reasons for the observed differences in metabolic behavior and drug interaction liability between the structurally similar oral anticoagulants warfarin and phenprocoumon were explored. Incubating (S)-phenprocoumon with human liver microsomes and cDNA-expressed CYP2C9 and determining its metabolism both in the absence and presence of the CYP2C9 inhibitor, sulfaphenazole, confirmed that phenprocoumon is a substrate for CYP2C9. Comparing the metabolic behavior of (S)- and (R)-warfarin, (S)- and (R)-phenprocoumon, and fixed structural mimics of the various tautomeric forms [(S)- and (R)-4-methoxyphenprocoumon, (S)- and (R)-2-methoxyphenprocoumon, (S)- and (R)-4-methoxywarfarin, (S)- and (R)-2-methoxywarfarin, and 9(S)- and 9(R)-cyclocoumarol] available to these two drugs with expressed CYP2C9 provides compelling evidence indicating that the ring closed form of (S)-warfarin and the ring opened anionic form of (S)-phenprocoumon are the major and specific structural forms of the two drugs that interact with the active site of CYP2C9. The conclusion that (S)-warfarin and (S)-phenprocoumon interact with CYP2C9 in very different structural states provides a clear basis for the significant differences observed in their metabolic profiles. Moreover, in accord with a previously established CoMFA model these results are consistent with the hypothesis that the active site of CYP2C9 possesses at least two major substrate binding sites, a pi-stacking site for aromatic rings and an ionic binding site for organic anions. An additional electrostatic binding site also appears to contribute to the orientation of coumarin analogs in the CYP2C9 active site by interacting with the C2-carbonyl group of the coumarin nucleus.

4-Hydroxycoumarins↗
PubMed1988

Biliary excretion of phenprocoumon and metabolites.

To evaluate phenprocoumon elimination its possible biliary excretion was evaluated in addition to the known pathway of renal elimination. Bile samples were obtained during diagnostic endoscopy in patients receiving chronic phenprocoumon therapy and were analyzed for phenprocoumon and its metabolites by HPLC and GC-MS. The following substances were detected, mainly in conjugated form: unchanged phenprocoumon and the metabolites 7-hydroxy-, 4'-hydroxy-, and 6-hydroxy-phenprocoumon. The data provide direct evidence of the biliary elimination of unchanged phenprocoumon and its metabolites in humans.

4-Hydroxycoumarins↗
PubMed1985

The effect of wheat bran on the pharmacokinetics of phenprocoumon in normal volunteers.

Observations of a variable anticoagulatory response in patients being treated by phenprocoumon and wheat bran resulted in a study of seven healthy volunteers. Up to 168 h after the administration of phenprocoumon, both in the fasting state and following the ingestion of 35 g wheat bran in a crossover design, blood samples were taken and urine was collected. The usual pharmacokinetic parameters were calculated from the concentrations measured. Following the ingestion of wheat bran, a decreased absorption rate for phenprocoumon but no decrease in overall bioavailability was observed. In addition, a decrease in total body clearance of phenprocoumon and an increase in the free plasma fraction of phenprocoumon, resulting in decreased free drug clearance, was seen after wheat bran administration. No differences were observed in the urinary excretion of either phenprocoumon or its metabolite. These findings cannot be completely explained by our present knowledge and need further investigation.

4-Hydroxycoumarins↗
PubMed1996

Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man.

OBJECTIVE: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. METHODS: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30-40% of normal within the first 5-9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11-15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. RESULTS: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95-1.09), thus fulfilling predetermined bioequivalence criteria (0.70-1.43). The pharmacokinetic characteristics AUC0-24h and Cmax of S(-)- and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC0-24h and of Cmax of S(-)-phenprocoumon (0.93, 0.87-1.00 for AUC0-24h; 0.95, 0.88-1.03 for Cmax) and of R(+)-phenprocoumon (0.89, 0.82-0.96; 0.9, 0.83-0.98) were within the accepted range of 0.8-1.25. CONCLUSION: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

[Phenprocoumon-induced necrotizing hepatitis].

CLINICAL PRESENTATION: A 52-year-old female patient presented at our hospital with right upper abdominal pain and impaired general condition. During the previous 7 months, the patient had received anticoagulation treatment with phenprocoumon due to a prosthetic aortic valve replacement. TESTS: Serological tests for virologic, autoimmune or metabolic causes of hepatitis were negative. The histologic examination of liver biopsies showed necrotizing hepatocellular injury in zone 3 of the acinus without relevant fibrosis. Initially, a lymphocyte transformation test with phenprocoumon was negative. A second test after one week turned out to be positive. DIAGNOSIS AND CLINICAL COURSE: After withdrawal from phenprocoumon therapy and switching to anticoagulation with a low molecular weight heparin, liver tests gradually became normal. Aminotransferase levels rapidly increased when phenprocoumon treatment was resumed. Phenprocoumon-associated necrotizing hepatitis was diagnosed by clinical course, liver histology and the positive lymphocyte transformation test. After immunosuppressive treatment with prednisolone was started again, liver enzymes gradually normalized. Anticoagulation was further performed with low molecular weight heparin. CONCLUSION: This case stresses the fact that an adequate and detailed history on concomitant medication is mandatory in patients who present with cryptic hepatitis. Though severe hepatic adverse effects of phenprocoumon are rare, physicians should consider coumarin derivatives as a potential source of hepatitis.

Anti-Inflammatory Agents↗
PubMed1980

[Observations in phenprocoumon (Marcumar) poisoning. Elimination and serum binding of the anticoagulant atatoxic blood concentration].

Serial serum concentrations of phenprocoumon were measured in 2 female patients who had taken 150 and 450 mg of the drug in suicidal attempts. In one case absorption of phenprocoumon took nearly two days. At a concentration of 1.7 and 1.8 microgram/ml the elimination curve showed a notch in both patients. Above this concentration half life was 97.7 and 95.9 hours, below these levels 134.4 and 155.5 hours. In-vitro binding investigations with serum of a healthy proband showed an increase of the non-bound drug by 56.6% at a phenprocoumon concentration of 0.5-25.34 micrograms/ml. As no notch could be observed at lower concentrations the notch in the elimination curve cannot be explained by concentration-dependent plasma binding of the anticoagulant. In-vitro experiments involving haemodialysis indicate that the letter cannot be recommended for treatment of phenprocoumon intoxication as the amount of phenprocoumon thus eliminated from the body is minimal. Both patients survived the phenprocoumon intoxication without damage. They were only treated with vitamin K.

4-Hydroxycoumarins↗
PubMed1990

Effect of oral contraceptive steroids on the pharmacokinetics of phenprocoumon.

1. The effect of chronic administration of oral contraceptive steroids (OCS) on the pharmacokinetics of the oral anticoagulant phenprocoumon was investigated in seven healthy females. 2. Plasma concentrations of phenprocoumon and the urinary recovery of unchanged as well as conjugated drug were measured following a single oral dose of 0.22 mg kg-1. A group of seven non-smoking, drug-free women matched for age and body weight served as controls. 3. Administration of OCS was associated with a significant increase in the clearance of phenprocoumon from 1.6 +/- 0.7 to 2.0 +/- 0.7 ml min-1 kg-1 (P less than 0.05). The urinary recovery of phenprocoumon glucuronide was significantly higher in OCS users (21.0 +/- 16 vs 14.0 +/- 10 (% of dose); P less than 0.05). No difference in plasma protein binding of phenprocoumon was observed, being 99.2 +/- 0.07 in both groups. 4. The accelerated glucuronidation of phenprocoumon in OCS users suggests the need for careful monitoring of the anticoagulatory response in these subjects, especially when the OCS are withdrawn.

4-Hydroxycoumarins↗
PubMed1996

Influence of fatty acids on the binding of warfarin and phenprocoumon to human serum albumin with relation to anticoagulant therapy.

Warfarin and phenprocoumon binding to human serum albumin was studied by equilibrium dialysis. The first stoichiometric binding constant was 1.89 x 10(5) M-1 for warfarin and 2.40 x 10(5) M-1 for phenprocoumon. The affinity of warfarin was markedly increased on addition of up to 3 mol mol-1 albumin of palmitic, stearic, oleic or linoleic acids with energetic couplings for co-binding of one molecule of each of the fatty acids and one molecule of warfarin of 0.9, 1.1, 0.7 and 0.6 kJ mol-1, respectively. The affinity of phenprocoumon was only increased slightly on addition of palmitate with an energetic coupling of 0.3 kJ mol-1. Six consecutive serum samples were obtained from each of 14 patients undergoing surgery. The serum affinity of the drugs varied considerably corresponding to free drug concentrations between 0.7 and 2.7% for warfarin and between 0.8 and 4.9% for phenprocoumon. The affinity of warfarin but not of phenprocoumon was correlated to the increasing plasma fatty acid concentration. Anticoagulant therapy with phenprocoumon may thus be less sensitive than warfarin to changes in the fatty acid concentration of plasma.

Anticoagulants↗
PubMed2005

Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol.

Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a racemate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors. Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9. In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

Acenocoumarol↗
PubMed2006

A single dose of oral vitamin K effectively reverses oral anticoagulation with phenprocoumon during heart catheterisation.

QUESTION UNDER STUDY: To investigate the effectiveness of a single adjusted dose of oral vitamin K to temporarily reverse oral anticoagulation with phenprocoumon (Marcoumar) for heart catheterisation. METHODS: Patients under stable oral anticoagulation with phenprocoumon routinely scheduled for heart catheterizstion were given a single adjusted dose of oral vitamin K a day prior to the intervention. The customary anticoagulation scheme was kept unchanged with the exception of taking the double usual dose of phenprocoumon the evening after the intervention. The primary outcome was the achieved international normalised ratio (INR) immediately before the intervention. Secondary outcomes were the INR after one and four weeks, changes in phenprocoumon and coagulation factors II and VII and adverse events. RESULTS: 38 patients at a median age of 71 (63-74) years scheduled for heart catheterisation were included. The median INR changed from 2.2 (1.9-2.6) the day before to 1.5 (1.4-1.7) immediately before the intervention. An INR < or =1.5 respectively < or =1.8 was achieved in 61% and 95% of the patients. The INR values after one respectively four weeks were comparable to preintervention values. No thromboembolic or bleeding adverse events occurred during the study. CONCLUSION: A single adjusted oral dose of vitamin K given a day prior to heart catheterisation combined with a doubled phenprocoumon dose on the procedure day seems to be an easy applicable, safe and effective way to temporary reverse oral anticoagulation with phenprocoumon.

Administration, Oral↗
PubMed1980

The German-Austrian aspirin trial: a comparison of acetylsalicylic acid, placebo and phenprocoumon in secondary prevention of myocardial infarction. On behalf of the German-Austrian Study Group.

In a multicenter clinical trial on the prevention of recurrent myocardial infarction, 946 patients who had survived a myocardial infarction for 30-42 days were randomly allocated to acetylsalicylic acid (ASA, 1.5 g/day) (317 patients), placebo (309 patients) or phenprocoumon treatment (320 patients) and were followed to determine the incidence of total mortality, coronary death and nonfatal recurrent myocardial infarction. The ASA and placebo groups were treated in double-blind fashion. The observation period for each patient was 2 years. Total mortality was lower in the ASA group (27 patients) than in the placebo (32 patients) and phenprocoumon groups (39 patients). There were 13 coronary deaths (fatal myocardial infarction and sudden death) in the ASA group, 22 in the placebo group and 26 in the phenprocoumon group. This represents a reduction rate of 42.3% in the ASA group compared with placebo (p less than 0.1) and of 46.3% in the ASA group with phenprocoumon (p approximately 0.07). Considering male patients alone, the difference regarding coronary death is significant between ASA vs placebo (p less than 0.05, reduction rate 56.4%) and ASA vs phenprocoumon (p less than 0.05, reduction rate 55.6%). Coronary events (coronary death and nonfatal recurrent myocardial infarctions) were lower in the ASA group (24 events) than in the placebo (37 events) (p less than 0.07) or phenprocoumon group (32 events).

4-Hydroxycoumarins↗
PubMed1996

[Possible potentiation of phenprocoumon by clarithromycin and roxithromycin].

Two patients, a women of 70 and a man of 75 years old, who were using phenprocoumon chronically, and were monitored by a regional thrombosis service, received a macrolide antibiotic, clarithromycin and roxithromycin respectively, for an airway infection. Both patients developed a serious increase in hypocoagulability, requiring administration of phytomenadione and temporary decreases in phenprocoumon dose. There were no bleeding complications. After the antibiotics were discontinued, the original dosage of phenprocoumon was needed again. It is suggested that in these patients the macrolide antibiotics may have potentiated the effect of phenprocoumon, perhaps as a result of inhibition of phenprocoumon transformation by liver enzymes. In patients receiving chronic treatment with phenprocoumon, coagulation parameters should be regularly checked if they are given a macrolide antibiotic such as clarithromycin, roxithromycin or erythromycin.

Aged↗
PubMed1996

Phenprocoumon for prevention of shunt occlusion after transjugular intrahepatic portosystemic stent shunt: a randomized trial.

Development of stenosis or occlusion of the transjugular intrahepatic portosystemic stent shunt (TIPSS) is one of the major limiting factors in the long-term viability of this procedure. The efficacy of anticoagulation with heparin which is used in different centers is still unclear. In the present study, we evaluated the effect of phenprocoumon on shunt patency after TIPSS placement using Palmaz stents; 49 patients with Child's A and B cirrhosis, who underwent successful TIPSS placement were randomized into the treatment group (n = 24) who received phenprocoumon and a control group (n = 25). After 11 to 13 weeks, all patients were admitted and had a reevaluation that included control angiography by transjugular approach. Phenprocoumon treatment was stopped after the first reevaluation and both groups were followed for 1 year after randomization. During the 3-month treatment period 11 of 22 patients of the treatment group and 12 of 23 patients of the control group required reintervention because of an increased portosystemic gradient. Five of the 12 patients in the control group showed complete occlusion of the shunt, whereas no occlusion in the treatment group was observed (P < .05). During the mean follow-up of 8 months after the treatment was stopped, in both groups stenosis occurred in 50% of patients, but no further occlusion of the stent was observed. These data indicate that occlusion of the stent is related to thrombosis, whereas stenosis does not appear to be dependent on blood coagulation. In patients with preserved liver function occlusion of the shunt may be prevented by phenprocoumon treatment in the first 3 months after TIPSS placement. Thereafter shunt occlusion was not observed and further phenprocoumon treatment seemed unnecessary.

Anticoagulants↗
PubMed1985

Metabolic fate of phenprocoumon in humans.

Samples of urine and feces were collected daily from a normal human volunteer who had received a dose of pseudoracemic phenprocoumon [an equimolar mixture of (R)-[12C]- and (S)-[2-13C]phenprocoumon] containing a tracer dose of 10 microCi of [14C]phenprocoumon and analyzed by TLC, HPLC, and GC-MS. After 25 days, 96% of the radiolabeled material was recovered (62.8% in urine and 33.3% in feces). By isotopic dilution and comparison to the Rf values, retention times, and mass fragmentograms of synthetic standards, the metabolites of the drug were identified as the 4'-, 6-, and 7-hydroxy analogues of phenprocoumon. Virtually all of the recovered radioactivity could be accounted for by the parent drug (approximately 40%) and the three metabolites (approximately 60%). The formation of both 4'-(8.1% of administered dose) and 7- (33.4% of administered dose) hydroxyphenprocoumon was highly stereoselective, giving S/R ratios of 2.86 and 1.69, respectively. The formation of 6- (15.5% of administered dose) hydroxyphenprocoumon showed little stereoselectivity (S/R ratio equal to 0.85). The urinary excretion pattern was also confirmed in four additional healthy male subjects who received a single oral dose of pseudoracemic phenprocoumon and whose urine was analyzed by GC-MS. All the drug-related materials (both hydroxylated metabolites and parent compound) that were excreted into the urine were extensively conjugated.

4-Hydroxycoumarins↗
PubMed2004

Determination of (R)- and (S)-phenprocoumon in human plasma by enantioselective liquid chromatography/electrospray ionisation tandem mass spectrometry.

Phenprocoumon is a commonly used oral anticoagulant of the coumarin type, and has found extensive clinical use in the treatment of thrombophlebitis, pulmonary embolism and atrial fibrillation. In the course of a clinical study to investigate the influence of genetic polymorphisms of the CYP2C9 enzyme on phenprocoumon metabolism, we developed a new enantioselective liquid chromatography/electrospray ionisation tandem mass spectrometry (LC/MS/MS) method to quantify (R)- and (S)-phenprocoumon in human plasma. HPLC separation of the enantiomers was achieved on a Chira-Grom-2 column under isocratic conditions using a water/acetonitrile/formic acid eluent. For detection and quantification a triple-quadrupole MS system was used in the selected reaction monitoring (SRM) mode. As an internal standard the structurally homologous compound warfarin was chosen. The detector response was linear with a correlation coefficient of 0.988-0.999 for (R)-phenprocoumon and 0.989-0.999 for (S)-phenprocoumon in the investigated concentration range between 62.5 and 1000 ng/mL (per enantiomer). The limit of detection (LOD) was 12.5 ng/mL.

Anticoagulants↗
PubMed1984

The effect of liver cirrhosis on the pharmacokinetics of phenprocoumon.

Phenprocoumon was given orally to 9 patients with biopsy proven liver cirrhosis (dose range 0.12-0.25 mg/kg) and to 7 healthy volunteers (0.23 mg/kg). Concentrations of phenprocoumon were determined using HPLC in plasma and urine samples obtained for 6-7 days after drug administration. The binding of [3H]-phenprocoumon in plasma from all subjects was determined by equilibrium dialysis. Antipyrine plasma concentrations were determined spectrophotometrically following oral administration of antipyrine (1200 mg). The total body clearance of phenprocoumon was higher in the cirrhotic patients (1.64 +/- 0.16 ml/h/kg mean +/- SEM) than in the healthy volunteers (0.90 +/- 0.07 ml/h/kg), however the free drug clearance was not significantly different in the patients (144 +/- 14 ml/h/kg) compared with normal (113 +/- 11 ml/h/kg). In contrast the clearance of antipyrine was much reduced in the cirrhotic group (17.5 +/- 2.9 ml/h/kg) compared with normal (35.6 +/- 3.9 ml/h/kg). The metabolic clearance of phenprocoumon via glucuronidation, is relatively unaffected during cirrhosis compared with antipyrine clearance via oxidation.

4-Hydroxycoumarins↗
PubMed1987

Factors responsible for interindividual differences in the dose requirement of phenprocoumon.

The total and unbound plasma concentrations of phenprocoumon and the prothrombin complex activity were determined in 51 patients on phenprocoumon. A 7-fold difference in the dosing rate (10-70 micrograms/kg/day) was required to maintain the prothrombin complex activity at 11-30% of normal. The variation in dosing requirement was mainly due to interindividual differences in the intrinsic clearance of phenprocoumon and only to a minor degree to differences in sensitivity to it. On average patients with myocardial infarction required only 2/3 of the daily dose of phenprocoumon of post cardiac surgery patients and patients with thrombosis and emboli. That difference appeared to be due to higher clearance in surgical patients and to greater resistance to phenprocoumon in patients with thrombosis and emboli. The total clearance in patients varied approximately 5-fold. It was better predicted by the interindividual intrinsic clearance (r = 0.84) than by the unbound fraction (r = 0.15).

4-Hydroxycoumarins↗