1997 Volume 12 Issue 1 Pages 48-57
[14C]menaquinone-4, a therapeutic agent for osteoporosis, was administered orally to male dogs at a dose of 4 mg/kg, and the absorption, distribution, metabolism and excretion were investigated.
1. The plasma concentration of radioactivity reached the maximum level (Cmax) of 4540.4 ng eq./ml at 1 to 2 hours after administration and thereafter decreased slowly. At Tmax, the unchanged menaquinone-4 in the plasma corresponded to 79.6% of the total radioactivity.
2. Within 168 hours, 2.3 and 78.1% of the radioa ctivity was excreted into the urine and feces, respectively. Unchanged menaquinone-4 corresponded to 28.5% of the radioactivity in the feces excreted within 24 hours.
3. The liver (33164.0 ng eq./g) and spleen (12542.2 ng eq./g) showed much higher concentrations of radioactivity than the other tissues and plasma (2994.5 ng eq./ml) at 1.5 hours after administration. The concentration in bile (109392.1 ng eq./ml) was also high, suggesting that the menaquinone-4 was immediately excreted into the bile. The elimination of radioactivity from tissues was relatively slow compared to that from plasma. In bone tissues, the target organ of the drug, the marrow (1424.9 ng eq./g) and cancellous tissue (2465.7 ng eq./g) of thighbone and the marrow (3533.4 ng eq./g) of ribs showed levels as high as the plasma concentrations at 1.5 hours and were 2 to 3 times higher than that of the plasma at 24 hours after dosing.
4. 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 after administration. The known metabolites, ω-COOH, K acid I and K acid II, were found in these tissues at 1.5 hours. In the adipose and cancellous tissue of thighbone, the unchanged menaquinone-4 was the major form up to 168 hours, while the relative amount of metabolites increased by 24 hours in the other tissues. Polar metabolites were found in the urine excreted within 24 hours and bile at 1.5 and 24 hours after administration. The unchanged menaquinone-4 was mainly found in the feces excreted within 24 hours.
5. The levels of radioactivity in the marrow and cancellous tissue of thighbone and the marrow of ribs at 1.5 and 24 hours after dosing (1.5 hours: 3.3−8.0×10-6 M, 24 hours: 1.9−3.1×10-6 M) were comparable to the pharmacologically effective concentrations of menaquinone-4 (10-6−10-5 M) in in vitro studies on bone formation. This finding suggests that menaquinone-4 distributes sufficiently into bone tissues after a single oral administration in dogs, and can be expected to maintain pharmacologically effective concentrations by repeated administration as a therapeutic agent for osteoporosis.