Europ. J.clin.Pharmacol. 8, 271-275 © by Springer-Verlag 1975

(1975)

Anticoagulant Effect and Plasma Kinetics of Fluorophenindione after a Single Dose in Man J.-P. Tillement,

J.J. Th~bault,

D~partment de Pharmacologie, de Cr~teil, France

C. Mattei, P. d'Athis,

and C. Blatrix

Facult~ de M~decine de Paris and Service de M~decine,

HSpital Intercommunal

Received: May 20, 1974, accepted: August 5, 1974

Summary. After administration of a single loading dose (80 mg p.o.) of fluorophenindione,

the prothrombin level decreased to 37 % in 24 h, and the effect lasted for 48 h. Accordingly, fluorophenindione can be classified as an anticoagulant with an "intermediate" effect. Its elimination half-life was 31 h, which is longer than that of phenindione, because of the greater stability of the fluorinated derivate.

Key words: Fluorophenindione,

vitamin K antagonist,

(Rumeau et 1972; Sabaut and Delvaux, 1972), p-fluorophenindione I (or fluorophenindione) has anticoagulant properties due to its antagonism to vitamin K. Chemically, it is close to the phenindione derivatives, but the stability of the hypocoagulahility it induces (Faivre and Neimann, 1972) relates it biologically rather to the coumarins. Like all vitamin K antagonists, its administration should follow definite rules. The initial or 'loading dose' is large (80 mg; 4 tablets) and is followed on subsequent days by smaller maintenance doses, which vary according to the biological result obtained from 20 to 40 mg per day. This therapeutic scheme has been generally accepted, although some authors consider that it should never be used because the larger, initial loading dose could be dangerous, i.e. it could be the cause of accidental haemorrhage (Len~gre and Gay, 1969). There are many justifications for this pattern of administration, both for any drug that is largely bound to plasma proteins, or that is related to vitamin K antagonists (Blatrix et al., 1968 a; O' Reilly and Aggeler, 1970; Tillement, 1974). Further, after administration of large single doses of vitamin K antagonists to man, we have never observed haemorrhagic accidents, regardless of the drug employed (Blatrix et al., 1968 b). It was important to know whether this would also apply to fluorophenindione. For this purpose the anticoagulant effect of a loading dose was measured and at the same time the ~ain parameters of its Recently introduced

into therapeutics

al., 1971; Dietz, 1972; Faivre and Neimann,

]Previscan®:

Nativelle Laboratories,

France

pharmacokinetics,

loading dose, anticoagulant.

plasma and urine kinetics were determined, together with the particular characteristics of the pharmaceutical formulation administered (tablets).

Materials and Methods Patients ~luorophenindione, as a single oral dose of 80 mg (4 tablets) was administered to six hospitalized patients, three men and three women, aged 30 to 55 years; weights 45 to 65 kg. The criterion for their selection were a therapeutic need for anticoagulant treatment (phlebitis), and the lack of clinical or laboratory evidence of hepatic disease and haematological or allergic disorders; in particular, prothrombin time, serum bilirubin, GOT, GPT and total proteins were normal. No other drugs were taken for 8 days before and during the test.

Blood Samples Blood samples are obtained by venepuncture at the following times: 0 (before administration of the anticoagulant), and after I, 2, 4, 8, 12, 24, 48, 72, 96 and 120 hours. Each sample (20 ml) was divided into two;~ one, mixed with Wintrobe's solution was used for measurement of Quick's clotting time (two tubes of 5 ml); the plasma concentration of fluorophenindione was measured in the other (10 ml in heparin).

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Urine was collected for 12 h periods before administration of fluorophenindione and for the following 72 hours. Analytical Techniques

Fig. 1. Model of two compartments used for computation

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Quick's time was measured according to the classical method (Quick, 1957). The determination was made on both of the two sample tubes. The result given is the mean of the two measurements, if they did not differ by more than one second. If this were not so, two other measurements on each tube were made and the result given as their mean. Final results have been expressed as percentages of normal. The normal values range from 90 to 1OO %. The therapeutic level is between 20 and 35 %. The concentration of fluorophenindione in plasma and urine was measured by U.V. spectrophotometry after extraction by toluene in an acid medium, according to the technique of Millar et al. (1968). The percentage of fluorophenindione bound to plasma proteins was measured by equilibrium dialysis according to a previously described method (Tillement et al., 1974).

2s Computation of the Pharmacokinetic Fluorophenindione 0

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Anticoagulant effect and plasma kinetics of fluorophenindione after a single dose in man.

After administration of a single loading dose (80 mg p.o.) of fluorophenindione, the prothrombin level decreased to 37% in 24 h, and the effect lasted...
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