The disposition of pitavastatin and pitavastatin lactone, which are mutually converted in the circulatory system, was investigated after intravenous administration of pitavastatin in dogs equipped with chronic bile-duct catheters. The plasma concentration of pitavastatin declined three-exponentially after dosing in the dogs with both diverted and non-diverted bile-flow. The terminal elimination half-life (T1/2) of pitavastatin in the diverted and non-diverted conditions was 3.12 and 5.01 hr, and that of pitavastatin lactone 4.50 and 7.23 hr, respectively. The diverted bile-flow decreased the AUC0-24 hr for pitavastatin and its lactone to 66 and 64%, respectively. In the dogs with the diverted bile-flow, 56.1% and 4.2% of the dose was recovered in the bile as pitavastatin and its lactone, respectively. The biliary clearance (CLb) of pitavastatin and its lactone was 32.5 and 6.8 mL/min, respectively, and the CLb of pitavastatin was about 4.8-fold that of its lactone. In the dogs whose bile-flow was not diverted, the cumulative biliary excretion of pitavastatin and its lactone was estimated from the AUC0-24 hr and CLb of both forms of pitavastatin. The estimated amount was increased by 46% compared with that in the dogs with the diverted bile-flow. This indicates that the increase reflects the actual contribution of the enterohepatic circulation.
In this study, the feto-placental transfer or excretion into the milk of SK-896 ([Leu13]motilin-Hse), a new human motilin analogue, were assessed after single intravenous injection of gestation or lactating female rats with 3H-SK-896. Two min after intravenous bolus injection of pregnant rats with 3H-SK-896 on the 12th and 18th day of gestation, respectively, the total radioactivity transferred to fetuses on the 18th day of gestation was higher than that on the 12th day of gestation, but both of them were less than 7% of maternal plasma. Furthermore, no immunoreactive radioactivity was detected 2 min and 30 min after administration in the fetal plasma on the 18th day of gestation, respectively. These results suggested that virtually no SK-896 is transferred to the fetus. After intravenous bolus injection of lactating rats with 3H-SK-896, the total radioactivity in the milk increased with time, reaching maximum 6 h after administration, and thereafter decreased. Although total radioactivity in the plasma was higher in the early stage after dosing, the milk-to-plasma concentration ratio rose with time, reaching 9.27 6 h after dosing. On the other hand, immunoreactive radioactivity was detected in the milk 15 min and 30 min after intravenous bolus injection, respectively, and 30 min after dosing the milk-to-plasma concentration ratio reached a maximum level of 1.59. But the immunoreactive radioactivity in the milk was eliminated rapidly and fell below the detection limit 1 h after dosing. With high performance liquid chromatography analysis of radioactivity in the milk, the peak of 3H-SK-896 was observed.
The absorption, distribution, metabolism, excretion and plasma protein binding of SNI-2011, a novel muscarinic acetylcholine receptor agonist developed as an agent improving the symptoms of dry mouth or dry eye caused by Sjögren's syndrome, were studied in rats. 1. After a single oral administration of 14C-SNI-2011 to male rats, plasma level of radioactivity reached the maximum at approximately 30 minutes, and declined by the bi-exponential manner. Oral absorption rate of radioactivity was 94%. Plasma level and pharmacokinetic parameters of radioactivity in female rats were comparable with those of male rats. 14C-SNI-2011 was considerably absorbed from duodenum, jejunum, ileum and colon. Plasma level of radioactivity at 8hr after daily oral administration of 14C-SNI-2011 increased with the number of dosing, and reached a steady state by the 3rd day. 2. After a single oral administration of 14C-SNI-2011 to male or female rats, radioactivity was distributed rapidly in whole body, and then eliminated rapidly. Tissue levels of radioactivity in male rats at 8hr after daily oral administration increased with the number of doses reaching approximately 4 times higher levels than those after the 1st administration. In pregnant rats on the 18th day of gestation, radioactivity was transferred into fetal tissues, and then decreased similarly as from maternal plasma. 3. SNI-2011 trans-sulfoxide (SNI-t-SO), SNI-2011 cis-sulfoxide (SNI-c-SO), SNI-2011 sulfone (SNI-SO2) and SNI-2011 N-oxide (SNI-NO) were identified in rat urine. As judged from the result on TLC/ radioluminography of plasma and urine samples, SNI-t-SO appeared to be the main metabolite in rats. Plasma concentration and urinary excretion rates of the unchanged SNI-2011 in female rats were higher than those in male rats. Repeated administration of SNI-2011 had no effect on liver weight, microsomal protein contents and activities of hepatic drug-metabolizing enzymes. 4. Main excretion route of 14C-SNI-2011 was urine in both of male and female rats, and approximately 100% of the dose was excreted in urine within 168 hours after administration. Fecal excretion rate of radioactivity was below 1% of the administered dose. Residual radioactivity in carcass accounted only for 0.1% of the dose. Daily urinary and fecal excretion rates of radioactivity in the period and after repeated oral administration were almost constant, and these rates were similar to those after a single administration. Radioactivity in the milk was 3.0 to 4.7 times higher than that in plasma. 5. Plasma protein binding rates of 14C-SNI-2011 in rats, dogs and human in vitro were relatively low (15.2 to 20.6%), and the binding rate was not affected by drug concentration or test species.
The absorption, excretion and metabolism of SNI-2011, a novel muscarinic acetylcholine receptor agonist developed as an agent improving the symptoms of dry mouth or dry eye caused by Sjögren's syndrome, were studied in dogs. 1. After a single oral administration of 14C-SNI-2011 to male dogs, blood and plasma level of radioactivity reached the maximum at approximately 1 hour, and declined by the bi-exponential manner. Blood and plasma half-lives of radioactivity in α phase were similar, however, blood half-life in β phase was longer than that observed in plasma. The distribution of radioactivity in blood cell was 27-54% up to 8 hours, and then increased with time reaching the values of more than 80% at 24 hours. 2. Cumulative excretion rates of radioactivity in urine and feces were approximately 95% and 0.7%, respectively, within 168 hours after administration, indicating that the main elimination route is the urinary tract. 3. Plasma concentrations of SNI-2011 N-oxide (SNI-NO) were 32 and 23 times higher in male and female dogs, respectively, than those of unchanged form. Main metabolite found in dog's urine was also SNI-NO. 4. There was no sex-related difference in blood and plasma concentration, excretion and metabolism of SNI-2011 in dogs after a single oral administration.