Pharmacokinetics and pharmacodynamics of two vitamin K1 formulations in rats.
OBJECTIVE
Severe allergic reactions associated with the commercially available formulation of vitamin K1 injection (VKI) could be a result of polysorbate that was added to solubilize vitamin K1 (VK1). Hence, we sought to develop vitamin K1 lipid emulsion (VKLE) devoid of polysorbate, in order to reduce the clinical risk of severe allergic reactions. This study aims to evaluate the pharmacokinetics and pharmacodynamics of VKLE in comparison to VKI in rats.


METHODS
Plasma concentration-time profiles of VK1 were investigated in rats after dosing VKLE or VKI at the range of 1-4 mg/kg. Tissue distribution of VKLE and VKI were investigated in rats at the dose of 2 mg/kg. The pharmacodynamics of VKLE and VKI were also studied by comparing their effects on coagulation factors (II/VII/IX/X) and prothrombin time in hypoprothrombinemic rats.


RESULTS
VKI demonstrated over-proportional increase in AUC at the dosage range of 1.0-4.0 mg/kg, whereas VKLE demonstrated a linear kinetics trend in general. Compared to VKI, VKLE could selectively deliver VK1 to the liver, spleen and heart. VKLE and VKI produced comparable maximal responses, in terms of coagulation factors and prothrombin time.


CONCLUSIONS
VKLE and VKI demonstrated different pharmacokinetics but comparable pharmacodynamics in rats.
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
L
L
Ma
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Y
Y
Cao
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
L
L
Chen
Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
Q
Q
Xiao
Clinical Pharmacology Modelling & Simulation, GSK China R&D, Shanghai, China.
J
J
Yang
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
J
J
Yang
D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004655:Emulsions / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006321:Heart / Q000502:physiology; D007700:Kinetics; D008055:Lipids / Q000008:administration & dosage / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D010837:Vitamin K 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D004655:Emulsions; D008055:Lipids; D010837:Vitamin K 1