scholarly journals Species Differences in Stereoselective Pharmacokinetics of HSG4112, A New Anti-Obesity Agent

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 127
Author(s):  
In Yong Bae ◽  
Min Sun Choi ◽  
Young Seok Ji ◽  
Sang-Ku Yoo ◽  
Kyungil Kim ◽  
...  
Keyword(s):  
Species Difference ◽  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Underlying Mechanism ◽  
Rat Plasma ◽  
Rat Liver Microsomes ◽  
Stereoselective Metabolism ◽  
Stereoselective Pharmacokinetics ◽  
The Difference ◽  
Dog Liver

HSG4112, a racemic drug, is a new anti-obesity agent. In this study, the stereoselective pharmacokinetics of HSG4112 were investigated in rats and dogs, and the underlying mechanism was investigated. The plasma concentrations of HSG4112(S) and HSG4112(R) were quantitated in plasma from rats and beagle dogs after IV and/or oral administration of racemic HSG4112. The concentration of HSG4112(S) was significantly higher than that of HSG4112(R) in rat plasma. Contrarily, the concentration of HSG4112(R) was significantly higher than HSG4112(S) in dog plasma. A metabolic stability test with liver microsomes showed that HSG4112(S) was more stable than HSG4112(R) in rat liver microsomes, but the difference between stereoisomers did not appear in dog liver microsomes. However, the stereoselectivity was observed in dog liver and intestinal microsomes after uridine 5’-diphospho-glucuronic acid was added. Thus, stereoselective metabolism by uridine 5’-diphospho-glucuronosyltransferases is mainly responsible for the stereoselective pharmacokinetics in dogs. These results suggest that the species difference in the stereoselective plasma pharmacokinetics of HSG4112 is due to the stereoselective metabolism.

scholarly journals Prediction of Hepatic Clearance of Stereoselective Metabolism of Carvedilol in Liver Microsomes and Hepatocytes of Sprague-Dawley and Cytochrome P450 2D-Deficient Dark Agouti Rats

2019 ◽  
Vol 22 ◽  
pp. 72-84
Author(s):  
Masahiro Iwaki ◽  
Toshiro Niwa ◽  
Hiroyuki Tanaka ◽  
Atsushi Kawase ◽  
Hiroshi Komura
Keyword(s):  
Plasma Concentrations ◽  
Liver Microsomes ◽  
Hepatic Clearance ◽  
Dark Agouti ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Stereoselective Metabolism ◽  
Sd Rats

Hepatic clearance (CLh) of carvedilol (CAR), which is eliminated via stereoselective metabolism by the CYP2D subfamily of cytochromes P450 (CYPs), was predicted using liver microsomes and hepatocytes from Sprague-Dawley (SD) rats and CYP2D-deficient Dark Agouti (DA) rats to determine the usefulness of prediction method. Plasma concentrations of CAR following intravenous injection to DA rats were higher than those in SD rats. The volume of distribution at steady state and total clearance (CLtot) of S-CAR were approximately two times greater than those of R-CAR in both strains. CLh predicted from in vitro studies using DA rat liver microsomes was different from that obtained from in vivo studies. In contrast, in vitro CLh prediction using DA rat hepatocytes was nearly identical to the CLh observed in DA rats in vivo, and was lower than that in SD rats. The predicted CLh in vitro using hepatocytes correlated well with the observed CLtot in vivo, which is expected to be nearly the same as CLh. These results suggest that in vitro metabolic studies using hepatocytes are more relevant with regard to stereoselectively predicting CLh of CAR than those using liver microsomes.

scholarly journals Metabolic Stability and Metabolite Characterization of Capilliposide B and Capilliposide C by LC–QTRAP–MS/MS

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 178 ◽  
Author(s):  
Zhongzhe Cheng ◽  
Xing Zhou ◽  
Zhifeng Du ◽  
Wenyi Li ◽  
Bingying Hu ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Species Difference ◽  
Liver Microsomes ◽  
Metabolic Stability ◽  
Rat Liver Microsomes ◽  
Triterpenoid Saponins ◽  
Additional Information

Capilliposide B (LC-B) and Capilliposide C (LC-C), two new triterpenoid saponins extracted from Lysimachia capillipes Hemsl, exhibit potential anticancer activity both in vitro and in vivo. However, their metabolic process remains unclear. In this study, the metabolic stability of LC-B, LC-C, and Capilliposide A (LC-A, a bioactive metabolite of LC-B and LC-C) was investigated in human, rat, and mouse liver microsomes, respectively. Thereafter, their metabolites were identified and characterized after oral administration in mice. As a result, species difference was found in the metabolic stability of LC-B and LC-C. All three compounds of interest were stable in human and rat liver microsomes, but LC-B and LC-C significantly degraded in mouse liver microsomes. The metabolic instability of LC-B and LC-C was mainly caused by esterolysis. Moreover, 19 metabolites were identified and characterized in mouse biological matrices. LC-B and LC-C mainly underwent deglycosylation and esterolysis, accompanied by dehydration, dehydrogenation, and hydroxylation as minor metabolic reactions. Finally, the metabolic pathway of LC-B and LC-C in mice was proposed. Our results updated the preclinical metabolism and disposition process of LC-B and LC-C, which provided additional information for better understanding efficacy and safety.

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