[Cholestyramine interrupts the enterohepatic circulation of phenprocoumon: a new therapeutic possibility in the treatment of phenprocoumon overdose].
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4-Hydroxycoumarins↗
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The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies.
The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct difference in the rate of elimination between the enantiomers. The apparent volume of distribution and the plasma clearance for S(-) phenprocoumon were less than those for R(+) phenprocoumon. When the binding of the enantiomers to human serum albumin was compared, S(-) phenprocoumon was more highly bound than R(+) phenprocoumon. The protein binding of racemic phenprocoumon was between that of the enantiomers. The results show that S(-) phenprocoumon is more potent anticoagulant than R(+) phenprocoumon and that the pharmacokinetic differences between the enantiomers are due mainly to differences in their distribution.
Adult↗
Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats.
The interaction of phenylbutazone with the enantiomers and racemic [3H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 microgram/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(-), and R, S(+/-) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained nearly unaffected by phenylbutazone. Thus there is no evidence for a stereoselective drug interaction between phenprocoumon and phenylbutazone. For racemic [oH]phenprocoumon it was possible to follow the kinetics of free drug in plasma and liver along with the time course of anticoagulant activity. In these studies, free drug concentrations in plasma and liver increased during treatment with phenylbutazone, but the elimination rate constant of free racemic phenprocoumon in plasma and liver remained essentially unchanged. Phenylbutazone markedly decreased the volume of distribution referenced to free drug and the clearance of free phenprocoumon (i.e., intrinsic metabolic clearance). Whereas the total (bound and unbound) drug concentration--effect relationship in plasma and liver was shifted to the left in rats treated with phenylbutazone, such shift was not seen in the free drug concentration--response relationship. In conclusion, the increase in the free concentration of phenprocoumon in plasma and liver and the concomitant decrease in the clearance of free drug are the mechanisms responsible for the marked and sustained enhancement of the anticoagulant effect which follows treatment with phenbutazone.
4-Hydroxycoumarins↗
[Elimination kinetics of phenprocoumon (Marcumar) in liver cirrhosis and after premedication with phenobarbital].
In this paper are presented the results of a study on the elimination kinetics of phenprocoumon in patients concomitantly treated with phenprocoumon and phenobarbital as well as in patients with bioptically proved hepatic cirrhosis. The pre-treatment of the patients with phenobarbital (3 X 100 mg), 4 days before phenprocoumon was started, resulted in an accelerated elimination of phenprocoumon. The biological half-life of phenprocoumon was reduced from 150 to 70 hrs when compared to normal controls, and the elimination constant was found to increase to 9,96 X 10(-3). Phenobarbital at plasma concentrations achieved by usual therapeutical dosage schedules of the drug does not interfere with the protein binding of phenprocoumon as could be shown by equilibrium dialysis. Phenobarbital, therefore, does not accelerate the elimination of phenprocoumon. The inducing effect of phenobarbital on the drug metabolizing enzyme system in the liver results in more rapid biotransformation of phenprocoumon. In patients with bioptically proved hepatic cirrhosis, the elimination kinetics did not differ from the results obtained in normal controls.
Adult↗
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↗
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↗
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↗
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↗
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↗
[Interaction of rifampicin with phenprocoumon (author's transl)].
Prothrombin time and plasma phenprocoumon levels were serially controlled, at short intervals, in three tubercular patients receiving both tuberculostatic drugs and phenprocoumon. The required phenprocoumon dose was continuously adapted to the prothrombin time values. During and after treatment with rifampicin optimal levels of prothrombin time were difficult or even impossible to achieve in two of the three patients. This confirms the known loss of effectiveness of the coumarins induced by rifampicin. This action has a slower onset and disappears more gradually than after acenocoumarol or warfarin. It is, therefore, likely that these two latter drugs are more suitable in patients treated with rifampicin than phenprocoumon.
4-Hydroxycoumarins↗
Collaborative study of a semiautomated method for the analysis of acenocoumarol, phenprocoumon, and potassium warfarin tablets.
This collaborative study was undertaken to determine if the anticoagulants acenocoumarol, phenprocoumon, and potassium warfarin could be analyzed by the automated analysis system described in the collaborative study for the analysis of sodium warfarin and dicumarol. Collaborators were supplied with a composited tablet sample of each anticoagulant. Results agreed well with the National Formulary methods for phenprocoumon and potassium warfarin, and an unpublished method for acenocoumarol. For acenocoumarol, coefficients of variation on individual sets of data ranged from 0.30 to 1.94% For phenprocoumon, coefficients of variation ranged from 0.52 to 1.20%. For potassium warfarin, coefficients of variation ranged from 0.54 to 1.79%. The results of this study show that acenocoumarol, phenprocoumon, and potassium warfarin can be analyzed by the official AOAC method for the analysis of sodium warfarin and dicumarol tablets.
Acenocoumarol↗
GLC determination of plasma concentrations of phenprocoumon.
A GLC method for the quantitative estimation of phenprocoumon from plasma is described. Plasma containing phenprocoumon, to which a known amount of phenytoin is added as the internal standard, is acidified and extracted with ethylene dichloride. The drug and the internal standard are then back-extracted into alkali, which is acidified and reextracted with ethylene dichloride. The organic extract is evaporated, and the evaporated residue is mixed with 50 mul of trimethylanilinium hydroxide in methanol. Aliquots (1-2 mul) are injected into a gas chromatography equipped with a flame-ionization detector in which the injection port is held at 325 degrees. The methyl derivatives of phenprocoumon and the internal standard give sharp, well-separated, symmetrical peaks. The method is of sufficient sensitivity to determine 0.125 mug/ml of the drug in plasma with a coefficient of variation of 7%.
Alkylating Agents↗
Double blind study of the effect of glafenine (Glifanan) on oral anticoagulant therapy with phenprocoumon (Marcumar).
The interaction between phenprocoumon (Marcumar) and glafenine (Glifanan) was investigated in a double blind study of twenty patients receiving long term treatment with phenprocoumon. Thrombotesttime (TT) values had been stable for more than three months before the study. Patients taking glafenine showed a significant increase in TT during the second and third week of the trial (P less than 0.05) compared with the placebo group. tthe increase in TT was not significant in the fourth week. The average concentrations of phenprocoumon were similar in both groups, which suggests that displacement of the drug from binding was not important. Concentrations of clotting factors II, VII and X showed a decrease in all patients at the time of the maximum TT values. A possible explanation for this interaction is discussed, but the mechanism remains uncertain.
4-Hydroxycoumarins↗
Phenprocoumon requirement, whole blood coagulation time, bleeding time and plasma gamma-GT in patients receiving mianserin.
A possible interaction between the tetracyclic antidepressant mianserin and a coumarin derivative has been investigated. Sixty-three subjects, 61 of whom required anticoagulant therapy for a variety of medical conditions, were treated for 5 consecutive weeks with phenprocoumon, in a dose adjusted to reduce the prothrombin time to 15%-25%. After an initial control period of one week, subjects were randomly treated under double-blind conditions with mianserin 3 X 10 mg daily or 3 X 20 mg daily, or with a matching placebo. The dose of mianserin was gradually increased to reach the maximum by the 6th day. Three subjects dropped out and 60 completed the trial. The dose of phenprocoumon and the prothrombin, bleeding, and coagulation times were not significantly affected by administration of mianserin. It can be concluded that there is no clinically important interaction between phenprocoumon and doses of mianserin effective in depression. Sedation was more frequent in patients taking mianserin than in those given placebo.
4-Hydroxycoumarins↗
[Studies on the interaction of Phenprocoumon with Diazepam and with Nitrazepam (author's transl)].
The influence of Diazepam and Nitrazepam on the anticoagulating activity of Phenprocoumon was studied in rats. It was found that the repeated oral application of Diazepam or Nitrazepam during the treatment with Phenprocoumon did not change the adjusted prothrombin time. The prothrombin time was considerably shortened when the application of Diazepam or Nitrazepam was stopped although Phenprocoumon was still applied. Furthermore, the influence of Chlordiazepoxid, Diazepam and Nitrazepam on the normal prothrombin time was studied. It was found that the treatment with benzodiazepine derivatives had no influence upon the prothrombin time, not only during the treatment, but also after the treatment was stopped.
4-Hydroxycoumarins↗
[Studies on the interactions of phenprocoumon with chlordiazepoxide in rats (author's transl)].
The influence of Chlordiazepoxide (Librium) on the anticoagulating activity of Phenprocoumon (Marcumar) was investigated in rats. It was found that this psychotropic drug influences neither the anticoagulating activity nor the normal prothrombin-time when it is applied alone or together with Phenprocoumon. However, the prothrombin-time is shortened when Chlordiazepoxide is withdrawn and the feeding of Phenprocoumon is continued.
4-Hydroxycoumarins↗
Determination of phenprocoumon, an anticoagulant, in human plasma.
Phenprocoumon is extracted from acidified plasma, the organic phase evaporated, and part of the residue, in ethanol, is quantitatively applied to a thin-layer plate. After separation, the quantity of phenprocoumon is assayed by fluorescence densitometry in situ. Results are reproducible to about 2.5%. The lower limit of detection is 0.1 mg/liter, which makes the method fully applicable to human plasma, because therapeutic concentrations range from 1 to 3 mg/liter. Seven determinations can be made within 3 h. For toxicological purposes, a qualitative analysis can be done in a shorter time, because the phenprocoumon spots are visible under ultraviolet light at 254 nm.
4-Hydroxycoumarins↗
Stereoselective effect of phenprocoumon enantiomers on the binding of benzodiazepines to human serum albumin.
The effect of phenprocoumon enantiomers on the stereoselective binding of 3-substituted 1,4-benzodiazepines to human serum albumin (HSA) was studied by chromatography on HSA-Sepharose column. (S)-Phenprocoumon exerts stereoselective allosteric interaction on the binding of benzodiazepines. The structural requirements of enhanced stereoselectivities are similar to those found previously with (S)-warfarin.
Benzodiazepines↗