Investigation on pharmacokinetics,tissue distribution and excretion of a novel anticancer platinum compound by inductively coupled plasma mass spectrometry after intravenous administration to rats

SM54111 [cis-3, 5-diisopropylsalylic cyclohexanodiaminoplatinum (II), Saliplatin] is a novel platinum compound with encouraging anticancer effect. In order to get more useful information in multiple species for the security evaluation, dosage design, and drug delivery design, its pharmacokinetic behaviors in rats after intravenous administration were investigated in this study. Based on its pharmacokinetics in plasma, the distribution of SM54111 in heart, liver, spleen, lung, kidney, brain, adipose, testicle, or ovaries of rats sampled at 0.5 h, 1 h, and 3 h after intravenous administration were determined utilizing inductively coupled plasma mass spectrometry (ICP-MS). Its amounts in urine and feces were determined at 8 sampling times till 96 h as well. It was proved that SM54111 fitted open two-compartment model in rats, with wide distribution in tissues and slow excretion. Its reasonable pharmacokinetic properties in rats make this novel platinum compound worthy of further research and development.     

Pharmacokinetics of NS-105, a novel cognition enhancer. 2nd communication: distribution and transfer into fetus and milk after single administration, and effects of repeated administration on pharmacokinetics and hepatic drug-metabolizing enzyme activities in rats

The tissue distribution and transfer into the fetus and milk of NS-105 ((+)-5-oxo-D-prolinepiperidinamide monohydrate, CAS 110958-19-5), a novel cognition enhancer, were investigated in rats after single oral administration of 14C-NS-105. The effects of repeated oral administration on the pharmacokinetics of NS-105 and hepatic drug-metabolizing enzyme activities also were investigated in rats. The radioactivity concentration in most tissues of male rats reached a maximum of 0.5 h after the single oral administration of 14C-NS-105, indicating rapid absorption and distribution, 0.5 h after the administration, the highest concentrations were present in the kidney and stomach, and the lowest in the white fat. The concentrations in the remaining tissues were moderately lower than the plasma value. The radioactivity concentrations in all the tissues tested decreased along with the plasma concentration, and were below or near the detection limit 24 h after the administration. Most of the radioactivity in the plasma, liver, kidney and cerebrum was due to unchanged NS-105. The tissue distribution patterns of radioactivity in female (non-pregnant) and pregnant rats after the oral administration of 14C-NS-105 did not differ from the pattern in male rats, revealing neither sex- nor pregnancy-related differences in NS-105 distribution. In pregnant rats, the maximum concentration in the fetus was 66% of that in the maternal plasma. In lactating rats, the radioactivity concentration in the milk was similar to that in the plasma. During and after the repeated oral administration of 14C-NS-105, the plasma concentrations and cumulative urinary and fecal excretions of radioactivity did not change with the number of administrations and were similar to the corresponding values after the single administration. The radioactivity concentrations in most tissues 8 h after the 7th, 14th and 21st administrations were about twice the corresponding values after the single administration, indicating that there is no marked accumulation of radioactivity in the tissues and that a steady state level was reached within 1 week. Repeated oral administration of NS-105 (10 mg/kg) to male rats did not affect hepatic drug-metabolizing enzyme activities.     

Pharmacokinetics of NS-49, a phenethylamine class alpha 1A-adrenoceptor agonist. 4th communication: tissue distribution, placental transfer and milk secretion of radioactivity in rats after a single oral administration of 14C-NS-49, and effects of repeated administration on its pharmacokinetics.

The tissue distribution, placental transfer and milk secretion of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoro-methanesulfonanilide hydrochloride, CAS 137431-04-0), a phenethylamine class alpha 1A-adrenoceptor agonist, have been studied after a single oral administration (1 mg/kg) of a suspension formulation to rats. Radioactivity concentrations in tissues were generally highest 1 or 4 h, and for most tissues, exceeded those in the corresponding plasma. Concentrations were generally similar in male and female rats and persisted for at least 24 h. Radioactivity concentrations in most tissues declined in parallel with those in plasma. Placental transfer of radioactivity was low accounting for < 0.1% of the maternal dose. In milk, concentrations were of a similar order to those in the plasma but reached a peak later: the data implied that 14C-NS-49 readily diffused from the plasma into the milk. The absorption, distribution and excretion of 14C-NS-49 have been studied after the repeated administration (1 mg/kg) of a suspension formulation to rats for up to 21 days. At 21 days, radioactivity concentrations in plasma reached a peak 1 h and declined with a terminal half-life of 67 h. Steady state concentrations were reached during 14 days. Peak concentrations in tissues occurred 1 h and, in most tissues exceeded the plasma value. Radioactivity concentrations in tissues appeared to reach steady state during the 21-day dosing period. Tissue and blood cell concentrations declined more slowly than those in the plasma. Radioactivity excretion was relatively constant during the repeated administration and similar in urine (mean 45.8% total dose) and feces (mean 48.2% total dose). At 7 days after the last of 21 daily oral doses, only 0.2% of the total dose remained in the body, indicating that there is no marked accumulation of radioactivity in the tissues. The results obtained in these studies indicated that rats receiving NS-49 at 24 h intervals during chronic and reproductive toxicity studies would be continually exposed to the parent compound and/or its metabolites.