Pharmacokinetics of the New Pyrimidine Derivative NS-7, a Novel Na+/Ca2+ Channel Blocker

Abstract

Tissue distribution, placental transfer and secretion of radioactivity in milk were studied after a single intravenous administration of 0.2 mg/kg of 14C-NS-7 (4-(fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride, CAS 178429-67-9), a novel Na+/Ca2+ channel blocker, to rats. Except for white fat in male and female rats, tissue radioactivity concentrations 5 min after administration were 2 to 100 times the plasma values, evidence that the drug is widely distributed throughout the body. Five minutes after administration the highest concentration was in the lung followed in order by the adrenal gland, kidney and thyroid gland. Concentrations in the cerebral cortex, striatum and cerebellum, the target organs of NS-7, were similar and 10 to 18 times the plasma concentrations in the male and female rats. Radioactivity concentrations in the lungs decreased rapidly. The pancreas had the highest concentration 2 h after administration. Concentrations decreased in all the tissues examined as the plasma concentration decreased. Maternal and fetal tissue radioactivity concentrations were determined after intravenous injection of 14C-NS-7 to pregnant rats on the 18th day of gestation. Radioactivity was well and rapidly distributed to the maternal tissues, and concentrations in all the tissues tested were higher than the plasma concentrations. In the amniotic fluid, however, the concentration was lower than in the plasma. In all the fetal tissues tested, radioactivity reached a maximum 1 h after administration. The respective fetal blood and whole body concentrations were 2 to 6 and 11 to 13 times the maternal plasma concentration. Of the fetal tissues tested the liver had the highest radioactivity. Decreases in fetal tissue radioactivity concentrations paralleled the decrease in the maternal plasma. More than 90% of the radioactivity present in the placenta and fetal whole body 1 and 24 h after administration was due to the unchanged drug. After intravenous injection of 14C-NS-7 (0.2 mg/kg) to lactating rats on the 10-14th day after parturition, radioactivity was excreted rapidly into the milk, reaching a maximum that was 4 to 6 times the plasma value 1 h after injection.