Pharmacokinetic characterization of menaquinone-4 in dogs by sensitive HPLC determination.
A simple and sensitive assay method for a pharmacokinetic study of Menaquinone-4 in dogs was established using HPLC with fluorescence detection following extraction with organic solvent. The quantification limit of this method was 1 ng/ml of plasma. A new oily solution formulation of Menaquinone-4 was administered orally to nonfasted dogs at doses of 0.4, 4 and 40 mg/kg. The plasma concentrations reached maximum levels at 1 to 1.5 h after dosing, and then decreased slowly. AUC values up to 24 h after administration were almost dose-proportional. Menaquinone-4 was also administered to dogs in soft-capsules, for comparison with a conventional hard-capsule oral formulation and an intravenous lecithin formulation. The mean AUC for oral dosing in the soft-capsule formulation was 13.5% of that for intravenous dosing in lecithin, and was 4.6 times higher than that for oral dosing in hard-capsules. Additional dosing in fasted dogs indicated that the AUC in pre-fed dogs was about 4 times higher, suggesting that feeding before giving Menaquinone-4 raises the bioavailability. Overall Menaquinone-4 was absorbed rapidly after administration in non-fasted dogs and dose-proportional bioavailability was obtained among the doses of 0.4 to 40 mg/kg. Higher plasma concentrations were observed after administration in the soft-capsule formulation rather than in the hard-capsule formulation. These findings suggest that the soft-capsule formulation would show a good pharmacokinetic profile for elderly patients with osteoporosis.
Sano
Y
Y
Tsukuba Research Laboratories, Eisai Co. Ltd., Japan.
Tadano
K
K
Kikuchi
K
K
Kaneko
K
K
Yuzuriha
T
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000502:physiology; D014812:Vitamin K / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D024482:Vitamin K 2 / Q000031:analogs & derivatives
D002214:Capsules; D024482:Vitamin K 2; D014812:Vitamin K; C030814:menatetrenone