Disposition of vitamin K 1 after intravenous and oral administration to subjects on phenprocoumon therapy

Abstract

The disposition and prothrombin-complex activity of a new i.v. dosage form of vitamin K 1 using mixed micelles of glycocholic acid and lecithin as a vitamin K 1 solution was studied in 9 volunteers on an oral phenprocoumon dosage regimen. Each of two volunteers received 10, 20, 40 or 60 mg i.v. and oral doses in a cross-over fashion. An additional subject received a single 60 mg i.v. bolus dose. The intravenous doses were well tolerated with no subjective or objective side-effects. Using a sensitive gas chromatographic assay (detection limit ≈ 5 ng/ml), the concentrations of vitamin K 1 could be followed for 24–36 h after the i.v. doses and for 12–33 h after the oral dose. The steady-state apparent volume of distribution was 20±6 liters and the clearance was 70±19 ml/min. The bioavailability demonstrated large inter-individual variation ranging from 3.5% to 60%. After the i.v. dose, vitamin K 1 showed multi-compartmental characteristics with a terminal half-life of 14±6 h. No dose dependency was detected in any of the pharmacokinetic parameters. The pharmacologic activity of vitamin K 1 after i.v. and oral dosing, defined as the area under the curve of the increase in the prothrombin-complex activity over baseline values during phenprocoumon therapy, correlated well with the logarithmic value of the area under the plasma concentration-time of vitamin K 1 ( r 2 = 0.677, t = 5.42, P < 0.001).