抄録
[14C]menaquinone-4, a therapeutic agent for osteoporosis, was administered orally to male dogs at a dose of 4 mg/kg once a day for seven days, and the absorption, distribution, metabolism and excretion were investigated.
1. The mean plasma concentration of radioactivity reached a maximum level at 1.5 hours after the 1st administration and thereafter decreased slowly. The concentrations at 1.5, 4 and 24 hours after each dose increased daily and approached a steady state by the 7th (final) dose, whereas constant plasma concentrations of unchanged menaquinone-4 were observed during repeated administration. The concentrations of radioactivity in erythrocytes increased during repeated administration and had not reached a steady state by the 7th dose.
2. The concentrations of radioactivity in the bile, liver, adipose, gall bladder and spleen at 1.5 hours after the final dose were 1.0, 0.9, 10.1, 0.6 and 1.2 fold, respectively, and were greater than those after a single dose. Radioactivity was highly accumulated in adipose tissues. In bone tissues, the target organ of the drug, the marrow and cancellous tissue of thighbone and the marrow of ribs showed higher concentrations than plasma levels at 1.5 hours, and were 3.7, 2.6 and 2.7 fold higher, respectively, than those after a single dose.
3. In urine and feces, 2.4 and 84.0% of the dosed radioactivity was excreted within 168 hours after the 7th dose, respectively. Unrecovered radioactivity was present in the adipose and other tissues at 168 hours.
4. The metabolic profile of [14C]menaquinone-4 after repeated administration was similar to that after single administration. The unchanged menaquinone-4 was the major form present in the plasma, liver, kidney, spleen, adrenal, adipose and cancellous tissue of thighbone at 1.5 hours and in feces excreted within 24 hours after the 7th dose. In the adipose and cancellous tissue of thighbone, the unchanged menaquinone-4 was the major form up to 168 hours, while the relative amounts of metabolites increased by 24 hours in the other tissues.
5. The levels of radioactivity in the marrow and cancellous tissue of thighbone and the marrow of ribs increased with repeated administration, and in the end were comparable to the pharmacologically effective concentrations of menaquinone-4 (10-6−10-5 M) observed in n vitroi studies on bone formation. It is, therefore, expected that repeated administration of menaquinone-4 may contribute to the pharmacological action of the drug as a treatment for osteoporosis.
