Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • The plasma clearance is the most crucial parameter determini

    2020-07-30

    The plasma clearance is the most crucial parameter determining the internal dose/systemic availability of any L-690,330 governing the biophase and other local tissue concentrations, responsible for exerting any effect or toxicity. Thus, the in vitro data generated was used to predict the in vivo clearance in rat and human. Using the degradation constant value obtained from log percent remaining versus time profile, the intrinsic clearance was calculated which was found to be 383.64 and 296.86 μL/min/mg protein in rat and human liver microsomes. The in vivo hepatic clearance predicted using the well-stirred model approach, 63.55 and 18.91 mL/min/kg in rat and human, respectively, was found to be close to the hepatic blood flow rate in both rat and human, suggesting it to be a high clearance compound (Davies and Morris, 1993). The in vivo studies conducted in rat in our lab also suggest that BNZ is a high clearance compound (data unpublished) as is indicated by the predicted in vivo hepatic clearance in this study. The extraction ratio was more than 0.9 in both the species. In general, the clearance of high extraction compounds is blood flow limited and thus, would not be affected by the phenotypic differences. Being blood flow limited, the clearance of BNZ could vary with changes in hepatic blood flow. Factors which decrease hepatic blood flow like aging, exercise and differences in posture could result in higher concentrations reaching systemic circulation as the clearance decreases. However, this inter-individual variability (30–40%) in hepatic blood flow would be accounted for in the default factor of 3.16 for individual variability in toxicokinetics to predict risk assessment in humans with confidence. Also, the high predicted in vivo hepatic clearance indicates that liver could be a major contributor towards the first pass metabolism of BNZ leading to its low oral bioavailability (internal dose) (Davies and Morris, 1993). This would be favorable in limiting the higher systemic concentration of BNZ when exposed through food and water. Confidence with which data of animal safety/toxicity studies can be translated to human depends upon the knowledge that whether humans would be exposed to similar chemical entities (parent and its metabolites) as the animals exposed during toxicity studies. In this regard, in vitro qualitative evaluation of interspecies difference in metabolite profile is important for selection of most appropriate animal species for toxicity studies which is close to human in terms of metabolite pattern. Thus, as majority of the toxicity studies are conducted in rats, in vitro metabolite profiles for BNZ were generated in human and rat for interspecies comparison (Whalley et al., 2017). Investigating the biotransformation pathways, reduction and oxidation were the major metabolic routes observed. Four oxidative metabolites and four reduced metabolites were formed in human liver microsomes. Similar metabolites were formed in rat liver microsomes as well, except that only two of the four reduced metabolites were observed and a single oxidative plus reduced metabolite was also observed in rat. These qualitatively different metabolites warrant further investigation to explore the metabolites formed in vivo upon systemic administration. In a qualitative study carried out by Das et al., seven metabolites of BNZ were identified when incubated with rat liver microsomes (Das et al., 1989). This commensurates with the findings of our present study. The inhibitory effect of BNZ on the activity of CYP isoforms was measured to evaluate the probability of CYP mediated metabolic interactions. BNZ was observed to have moderate inhibitory effect only on CYP1A2 with IC50 value of 5.82 μM. Such high systemic levels are very unlikely to be reached upon environmental exposure, thus reducing the possibility of metabolic interactions upon co-exposure with other xenobiotics. Similar findings have also been reported in a study conducted by Das et al. where BNZ was found to be an inhibitor of hepatic aminopyrine N-demethylase and ethoxyresorufin-O-deethylase activities, both in vitro and in vivo, in rat. However, these inhibitory effects were observed at relatively higher concentrations (Das et al., 1991). The weak inhibitory effect of BNZ on CYP isoforms further reduces the uncertainty in assessing the risk of BNZ exposure in humans.