The pharmacokinetics and the pharmacological effects of the deleted form of hepatocyte growth factor (dHGF) after intravenous (iv), subcutaneous (sc), or intramuscular (im) administration (0.25 and 2. 5 mg/kg) were studied in rats. After single iv administration (2.5 mg/kg), dHGF in serum rapidly decreased (alpha- and beta-phase half-life: 3.2 and 26.5 min, respectively). Two to four hours after single sc or im administration (2.5 mg/kg), the serum level of dHGF reached a maximum and then gradually declined (half-life: 2.7 h). The serum levels were not changed by repetitive iv administration, but were dramatically decreased by repetitive sc or im administration. Liver weight and serum levels of total protein, albumin, and HDL-cholesterol were significantly increased by iv administration of dHGF (twice daily for 4 days at 0.25 mg/kg). Sc or im administration of dHGF did not increase these parameters at the same dose, but did significantly at 2.5 mg/kg. These observations suggest that iv administration is the most effective in exerting the pharmacological effects of dHGF among three administration routes. dHGF after iv administration was distributed mainly and rapidly into liver (53.6% of the injected dHGF within 5 min) and was sustained at a higher level in the liver than in plasma. In infusion (0.5 mg/kg/3 h), dHGF level in plasma and liver reached a steady-state 15 and 60 min after starting the infusion, respectively. The steady-state level of dHGF was 7- to 9-fold higher in liver than in plasma, and the higher level in liver was sustained beyond the steady-state.
In this study, the pharmacokinetics of SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjögren's syndrome, in rats and dogs were determined following intravenous or oral administration using liquid chromatography/mass spectrometry (LC/MS). The in vitro metabolism of SNI-2011 was also evaluated with rat and dog liver microsomes. After oral administration, plasma concentrations of SNI-2011 reached to Cmax within 1 h in both species, suggesting that SNI-2011 was quickly absorbed, and then decreased with a t1/2 of 0.4-1.1 h. The bioavailability was approximately 50% and 30% in rats and dogs, respectively. Major metabolites in plasma were both S- and N-oxidized metabolites in rats and only N-oxidized metabolite in dogs, indicating that a large species difference was observed in the metabolism of SNI-2011. Sex difference was also observed in the pharmacokinetics of SNI-2011 in rats, but not in dogs. In the in vitro study, chemical inhibition and pH-dependent studies revealed that the sulf-oxidation and N-oxidation of SNI-2011 were mediated by cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), respectively, in both species. In addition, CYP2D and CYP3A were mainly responsible for the sulfoxidation in rat liver microsomes.
The pharmacokinetics and metabolism of SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjögen's syndrome, were investigated in six healthy volunteers after a single oral administration of 14C-SNI-2011. After administration, plasma concentrations of the radioactivity and SNI-2011 reached to Cmax at approximately 2 h, and then decreased with t 1/2 of 9 and 4 h, respectively. Cmax and AUC0-infinity of the radioactivity in plasma were 2.2 and 5.0 times higher than those of SNI-2011, respectively. The main excretion route of the radioactivity was urine, and 97.3% of the dose excreted in urine within 168 h, indicating that 14C-SNI-2011 was completely absorbed. The mean recoveries of the metabolites in urine at 24 h after administration were 16.0% for SNI-2011, 35.8% for SNI-2011 trans-sulfoxide (SNI-t-SO), 8.7% for SNI-2011 cis-sulfoxide, 4.1% for SNI-2011 N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of SNI-2011 and SNI-t-SO, respectively.
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