［｀１４´Ｃ］ＮＢ‐５０６の体内動態　ラットにおける単回および反復静脈内投与後の血しょう中動態，分布，代謝および排せつ

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  • Studies on the disposion of (14C)NB-506: Plasma Concentration-Time Profile, Distribution, Metabolism and Excretion of (14C)NB-506 after Single and Repeated Intravenous Administration in Rats.

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Plasma concentration-time profile, distribution, metabolism and excretion of [14C]NB-506 were investigated in male and female rats after single and repeated intravenous administration.<BR> 1. After a single intravenous administration of [14C]NB-506 to male rats, plasma levels of radioactivity decreased triexponentially with the t1/2 of 22 min, 2.4 hr and 2.1 day. The pharmacokinetic parameters obtained from female rats, were similar to those in male rats.<BR> 2. After a single intravenous administration of [14C]NB-506 to male rats, the maximum concentration in almost all tissues was observed at 10 min. The radioactivity was highly distributed in liver followed by kidney, lung, mandibular gland, skin and pancreas. At 24 hr post dose, the radioactivities in tissues were almost same as that of plasma except liver and kidney, and then decreased and were lower than 10% of maximum radioactivity at 72 hr.<BR> 3. Within 120 hr after a single intravenous administration of [14C]NB-506 to male rats, 9.8 and 88.3% of dose were excreted into urine and feces, respectively. Biliary excretion was 82.9% in male rats. The enterohepatic circulation of [14C]NB-506 was not observed in male rats. The excretion of radioactivity in female rats was similar to that in male rats.<BR> 4. After a single intravenous administration of [14C]NB-506 to male rats, 40.0, 23.8, 6.3 and 1.5% of dose were excreted to bile (0-6 hr) as intact NB-506, NB-506 glucuronide (ED-594), NB-506 deformyl form (ED-501) and ED-501 glucuronide (ED-595), respectively. The 6.2% of administered dose in urine (0-4 hr) corresponded to intact NB-506 and 0.7% of dose was excreted to urine as ED-594 and ED-501.<BR> 5. The plasma levels of radioactivity at 5 min, 4, 24 hr after the 5th dosing were higher than those after the first dosing. Moreover, the levels of AUC(0-∞) and t1/2γ of the 5th dosing were 2.1 and 2.3 times higher than those of the first dosing, respectively. These results indicate that [14C]NB-506 tend to accumulate in plasma after the multiple dosing. The accumulation ratio was calculated based on the plasma levels of radioactivity at 24 hr after the first and the 5th dosing; this value was 3.85. On the other hand, the accumulation factor, which was estimated from the elimination rate constant, was calculated to be 3.56. Therefore, the accumulation ratio was almost of the same value as the predicted accumulation factor. These results suggest that it is possible to predict the disposition of [14C]NB-506 after the multiple dosing and the possibility that the crucial accumulation of [14C]NB-506 may arise from the multiple dosing is low.<BR> 6. No change in the daily excretion of radioactivity in urine and feces was observed during 5-day repeated administration. Within 168 hr after the last dosing, urinary and fecal excretion of radioactivity were 7.5 and 90.1% of dose, respectively, indicating that the main elimination route is fecal excretion.

収録刊行物

  • 薬物動態

    薬物動態 13 (4), 337-345, 1998

    日本薬物動態学会

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