The plasma level, tissue level, brain distribution and excretion of the radioactivity were investigated in rats after intravenous administration of [¹⁴C]posatirelin at a dose of 20 mg/kg.
1. The plasma level of radioactivity at 5 min after intravenous administration was about 71 μg eq·/mll, and decreased biphasically thereafter with half lives of about 18 min (α-phase) and 15 hr (β-phase). The AUC (0-∞) was about 47 μg eq·hr/ml.
2. At 5 min after administration, the kidney showed the highest level of radioactivity, followed by the plasma, aorta, urinary bladder, skin, pancreas, liver and lung. The brain level of radioactivity was the lowest among the tissue levels examined. Most tissue levels decreased essentially in parallel with plasma level.
3. At 5 min after administration, the mesolimbic area and cerebellum levels of radioactivity we re significantly higher than those in other parts of the brain. The cerebral cortex, cerebellar cortex, fornix, triangularis septal nucleus, hippocampal commissure, colliculus superior and ventricle wall were found to exerthigh levels of the radioactivity.
4. The cumulat ive excretion of radioactivity in urine, feces and expired air were 70.9%, 12.3% and 15.1%, respectively, within 72 hr after administration. Within 48 hr after administration, 7.2% of dosed radioactivity was excreted in the bile.
5. [¹⁴C]Posatirelin was hardly bound to rat plasma and human serum proteins.

View full abstract

The transfer of radioactivity into the fetus and milk was studied in pregnant and lactating rats, respectively, after a single intravenous administration of [¹⁴C]posatirelin. The plasma level, tissue distribution and excretion of radioactivity were investigated in male rats after 21 consecutive daily intravenous administration of [¹⁴C]posatirelin at a dose of 20 mg/kg/day.
1. The fetal concentrations of radioactivity reached the maximum level at 1 hr after dosing, which was about 15% of the maternal plasma concentrations. The fetal concentrations of radioactivity at 48 hr after dosing were about 6 % of the levels in fetus at 1 hr after administration.
2. The levels of radioactivity in the milk reached ap proximately 4.6 μg eq./ml at 1 hr after administration, decreased thereafter with the half life of 5.8 hr. After 6 hr, the milk levels were 3-6 times higher than the corresponding plasma levels.
3. The plasma levels of the radioactivity at 5 min after every dosing were at virtually plateau level of 53-78 μg eq./ml. Those at 24 hr after every dosing increased gradually until 6 days, and reached the plateau level of 0.20-0.34 μg eq./ml thereafter. The plasma levels after the final dosing decreased biphasically with the half lives of about 17 min (α-phase) and about 46 hr (β-phase). The AUC_(0-∞) after the final dosing was about 54 μg eq.·hr/ml, which was not of statistically significant different from that after single administration.
4. Among the tissues and organs studied, the kidney showed the highest level of radioactivity at 5 min after repeated administration. In most tissues, the radioactivities were eliminated rapidly until 24 hr after administration but thereafter, the radioactivities decreased slowly.
5. During the period of repeated administration, the ex cretion of the radioactivity in the urine, feces and expired air were of almost constant values of 72-80%, 10-11% and 9-12%, respectively.

View full abstract

After a single or repeated intravenous administration of [¹⁴C]posatirelin in rats, the structure of urinary metabolites and the metabolite profile of plasma, urine, bile and milk were studied.
1. In 24 hr urine of rats, three major radioactive components were detected on thin layer chromatogram. One component was identified by mass spectrometry as the unchanged posatirelin. Other components were (2S)-6-oxopipecolic acid (M2) and (2S)-N-[(1S)-1-[[(2S)-2-carboxyl-1-pyrrolidinyl]carbonyl]-3-methylbutyl]-6-oxopipecolamide (M3) as revealed by mass spectrometry.
2. In plasma at 1 hr after single administration, the unchanged posatirelin, M2 and M3 were accounted for about 40%, 36% and 21%, respectively.
3. The unchanged posatirelin, M2 and M3 accounted for about 61%, 18% and 18%, repectively, of radioactivity in 24 hr-pooled urine.
4. After repeated adminis tration, the composition of plasma and urinary radioactive metabolites were not statistically different from those after single dosing.
5. M3, unchanged posatirelin and M2 accounted for about 88%, 8% and 5%, respectively, of radioactivity in 24 hr-pooled bile.
6. In milk at 1 hr a fter administration, the unchanged posatirelin, M2 and M3 were accounted for about 84%, 8% and 9%, respectively.

View full abstract

We introduces three examples for drug interactions from literatures, i.e. terfenadine, grapefruit juice, and cyclosporin A, as well as one from our drug candidate for subarachnoidal hemorrage, tirilazad. It is still difficult to estimate extent of drug-drug interactions related to drug metabolism even by in vitro studies using human liver preparations. It must be necessary to obtain more data on relationships between the in vitro and in vivo study results for estimation of the possibility and extent of the interactions. Recently, drug interactions related to protein binding are not regarded as an important issue in Europe and USA from the reasons: 1) it was shown that historical examples for protein binding drug-drug interactions were caused by inhibition of the metabolism etc., which are other than protein binding, 2) The pharmacokinetic theory also supports the idea. It must be necessary to establish a common principle for this issue between Japan and Europe-USA.

View full abstract