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.
Absorption, distribution, metabolism and excretion after a single intravenous and oral administration of [14C]urea at a dose of 2 mg/kg were investigated in fasted rats. 1. Both radioactivity levels in plasma after intravenous and oral administration of [14C]urea were decreased biphasically with t1/2α of about 2.0 hr and t1/2β of about 3.5 hr. After oral administration, the plasma concentration reached Cmax at 0.5 hr, suggesting rapid absorption of urea in the gastrointestinal tract. 2. Radioactivity levels in most tissues reached Cmax at 0.5 hr after oral administration, similar to that observed in the plasma. Excluding the radioactivity present in the digestive tract where [14C]urea was administered, the concentrations in the kidney and urinary bladder were the highest in the examined tissues and were 3.2 and 2.5 times as high as that in plasma. The concentrations in other tissues were similar to, or lower than the plasma concentration. Subsequently, the concentrations in most tissues rapidly decreased in parallel with the plasma concentration. 3. In plasma at 0.5 hr and 8 hr after oral administration and in the urine collected for 24 hr after intravenous and oral administration, the major component of radioactivity was the unchanged drug and other metabolites were not observed. One may concluded that urea was almost not metabolized in fasted rats, considering the results of the excretion study, in which more than about 90% of dose radioactivity was excreted in urine as unchanged drug. 4. Within 96 hr, 91.1%, 0.3% and 4.7% of dosed radioactivity were excreted in urine, feces and expired air after intravenous administration, and 95.1%, 1.2% and 3.5% after oral administration, respectively. The bioavailability estimated from the ratio of urinary excretion of urea after oral administration to that after intravenous administration was almost 100%.
Absorption, distribution, metabolism and excretion after a single intravenous and oral administration of [14C]urea at a main dose of 2 mg/kg were investigated in non-fasted rats. Comparison of the pharmacokinetics in rats between under non-fasted and fasted conditions was also investigated. 1. The radioactivity levels in plasma were decreased biphasically with t1/2α of 2-3 hr and t1/2β of 6-11 hr, irrespective of administration routes and doses. After oral administration at doses of 2, 62.5, 250 and 1000 mg /kg, the Cmax and AUC0-∞ were virtually proportional to the administered doses, suggesting linear-pharmacokinetics within the examined dose range. 2. The radioactivity levels in plasma and tissues reached Cmax at 0.5-1 hr after oral administration. The concentration in the kidney, which was 2.4 times as high as that in plasma, was the highest in the examined tissues. The concentrations in other tissues were similar to, or lower than the plasma concentration. After the Cmax, the concentrations in most tissues decreased in almost parallel with the plasma concentration. 3. In plasma at 1 hr after oral administration, only the unchanged drug was observed in the plasma radioactivity. On the other hand, at 8 hr, about 70% and 30% of the plasma radioactivity were unchanged drug and unknown components, respectively. In urine for 24 hr after dosing, only the unchanged drug was also observed, irrespective of administration routes. 4. Within 96 hr, 73.1%, 1.6% and 20.1% of dosed radioactivity were excreted in urine, feces and expired air after intravenous administration, and 54.0%, 1.0% and 42.9% after oral administration, respectively. The bioavailability estimated from the ratio of urinary excretion of urea after oral administration to that after intravenous administration was 74%. 5. Feeding condition in rats enhanced metabolism/decomposition of urea and influenced its plasma concentration-time profiles and excretion profile.
Feto-placental transfer and excretion into milk were investigated in pregnant rats under fasted conditions and lactating rats under non-fasted conditions after a single oral administration of [14C]urea at a dose of 2 mg/kg. 1. The radioactivity levels in the placenta and fetus were about 1/2 of the maternal plasma concentration and those in the maternal tissues, excluding the stomach, kidney and urinary bladder, were similar to, or lower than the maternal plasma concentration. The observation of whole body autoradiogram at 24 hr after administration showed that the radioactivity had decreased rapidly from the fetus. 2. At 30 min after administration, the radioactivity levels in the plasma and milk reached Cmax, and the ratio of the milk to the plasma concentration was 0.8. The major component in the milk and plasma was the unchanged drug. After Cmax, the plasma concentration decreased monophasically with t1/2α of 1.6 hr and the milk concentration decreased biphasically with t1/2α of 1.8 hr and t1/2β of 8.2 hr.
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.
The species of enzymes involved in human metabolism of quazepam and its metabolites M4 and M6 were clarified, and the effects of these compounds on activities of major human P450 isozymes were also evaluated. To identify the CYP isozymes involved, nine kinds of cDNA-expressed human CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11) were used to clarify each metabolic reaction. Moreover, inhibitory study was performed to identify the major CYP isozymes responsible for the metabolism of each compound, using human liver microsomes as the enzyme sources, anti-P450 antibodies and anti-P450 antiserum. In addition, flavin-containing monooxygenase (FMO) was examined for its involvement in the metabolism of quazepam to M4. The results revealed that the metabolism of quazepam to M4 was catalyzed by two CYP isozymes, i.e. CYP2C9 and CYP3A4. FMO was found not to be involved in this reaction. The metabolism from M4 to M5 and from M4 to M6 was catalyzed by CYP3A4 and mainly by CYP2C9 and CYP3A4, respectively. Furthermore, M6 was found to be metabolized to M7 by CYP3A4. Next, quazepam, M4, and M6 were examined for their inhibitory effects on the metabolic activities of major human drug metabolizing CYPs (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Here, cDNA-expressed human CYPs as enzyme sources and typical substrates for each CYP isozymes were used. The results indicated that each of these compounds has little effects on the metabolic activities of all the CYP isozymes studied.
The Pharmacokinetics of 3H-BN·HCl in male rats was studied after a single percutaneous (3HTSN-09 : 3H-BN·HCl containing tape) or subcutaneous administration of 3H-BN·HCl. 1. The radioactivity level in blood reached the Cmax at 21.6 hr after a single percutaneous administration, then decreased with the t1/2 of 4.8 days, and the unchanged drug concentration in plasma reached the Cmax at 8 hr after dosing. When 3H-BN·HC1 was administered percutaneously as a tape formulation (3H-TSN-09) at the dosage of 20, 40 or 80μg of 3H-BN·HCl/animal, the Cmax and AUC0-∞ value increased in proportion to the administered dose. From the AUC0-∞ values in percutaneous and subcutaneous administration, the absorption ratio of percutaneous administration was calculated to account for about 14% of dose. The Tmax of each dose was observed at around the end of application period, indicating the absorption of 3H-BN·HCl through skin to continue during application period. 2. When 3H-TSN-09 was applied to the shaved area skin in rats, the whole body autoradiogram showed high level of radioactivity of the application site of the skin, low level of radioactivity in the gastro-intestinal contents and little level of radioactivity in most other tissues. 3. Within 168 hr after a single percutaneous administration, 1.0 and 8.2% of dose was excreted into urine and feces, respectively. 4. The binding of BN·HCl to plasma protein varied from 88.9 to 97.4% in rat, dog or human. BN·HCl bound to human serum albumin, γ-globulin and α1-acid glycoprotein and their binding ratios were 65.5, 41.5 and 84.9%, respectively. 5. After a single percutaneous administration of 3H-BN·HCl to rats, two metabolites, RP1 and RP2 were detected in plasma. The structures of RP1 and RP2 were identified as norbuprenorphine-glucuronide and BN-glucuronide, respectively. These two metabolites were also found in rat plasma after a single subcutaneous administration. So it was considered that the metabolic pathway of BN·HCl might be the same in both administration routes.
The role of stratum corneum in percutaneous absorption of BN·HCl was investigated (3H-TSN-09 tape; 4×4 cm, BN·HCl content is 20μg/sheet) in a model of normal or damaged skin rats. 1. The microautoradiograms of skin at 8 hr after percutaneous administration of 3H-BN·HCl as a tape formulation (3H-TSN-09) in normal skin rats showed that the radioactivity was predominantly distributed in the stratum corneum. 2. After percutaneous administration of 3H-BN·HCl to damaged skin rats, the radioactivity concentration in the blood reached the Cmax at 5 hr and then decreased with the t1/2 of 5.5 days. And the AUC0-∞ value was about 4 times higher than that in normal skin rats. 3. After percutaneous administration of 3H-BN·HCl to damaged skin rats, the coefficient of variation of the Cmax was about one-third of that in normal skin rats. 4. It was considered that 3H-BN HCl was mainly absorbed by transcellular route and the stratum corneum played important role in percutaneous absorption of 3H-BN·HCl as evidenced by; i) decreasing the absorption of 3H-BN·HCl and ii) causing inter-individual difference in blood radioactivity.
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