Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats

Abstract

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.

Plasma protein binding of azapropazone in patients with kidney and liver disease.

“…The plasma protein binding of [3H]-phenprocoumon was determined as described earlier (Schmidt & Jahnchen, 1979). The binding of azapropazone to albumin was determined using a commercially available human serum albumin preparation (dried, purified, electrophoretic purity 100%; Behringwerke AG, Marburg, Germany).…”

“…The situation seems to be even more complicated in patients with liver disease (Affrime & Reidenberg, 1975;Klotz, 1976;PerezMateo & Erill, 1977;Blaschke, 1977;Tillement et al, 1978 (Schmidt & Jahnchen, 1979). The binding of azapropazone to albumin was determined using a commercially available human serum albumin preparation (dried, purified, electrophoretic purity 100%; Behringwerke AG, Marburg, Germany).…”

Concentrations of Phenprocoumon in Serum and Serum Water Determined by High-Performance Liquid Chromatography in Patients on Oral Anticoagulant Therapy

“…Sev eral methods have been proposed for the de termination of PPC concentrations in blood. They are based on fluorometry [9][10][11], thinlayer chromatography [12], gas chromatogra phy [13,14] and high-performance liquid chromatography (HPLC) [2][3][4][5]7,[15][16][17]. The fluorometric and thin-layer chromatography assays generally were found to have insuffi cient specificity and sensitivity.…”

“…in cases of resistance of the patient to PPC, suspected intoxication or noncom pliance. Furthermore the pharmacokinetics of PPC can be altered by coadministered drugs that accelerate PPC metabolism or dis place the anticoagulant from serum proteins thereby increasing its unbound fraction in serum water (SW-PPC) [8,9], The latter leads to an increase in the anticoagulant effect of PPC. Therefore it may be useful to supple ment the determination of S-PPC by the mea surement of the SW-PPC concentration.…”

Sex-related Differences in Disposition and Response to Phenprocoumon in Rats

“…Protein binding. Serum protein binding was determined in the rat serum obtained at the end of the study, using an equilibrium dialysis technique described earlier (Schmidt & Jahnchen 1979). line, the apparent volume of distribution (V) from the backextrapolated zero time concentration and the clearance (CL) from the i.v.…”