Characterization of human hepatocytes by quantitative dmet proteomics addresses lot-to-lot variability: relevance in In-vitro to In-vivo extrapolation of hepatic drug clearance

2019 ◽  
Vol 34 (1) ◽  
pp. S23-S24
Author(s):  
Bhagwat Prasad ◽  
Haeyoung Zhang ◽  
Deepak Bhatt ◽  
Abdul Basit ◽  
Maureen Bunger
Keyword(s):  
Drug Clearance ◽  
Human Hepatocytes ◽  
Hepatic Drug ◽  
In Vivo Extrapolation

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

2012 ◽  
Vol 40 (5) ◽  
pp. 982-989 ◽  
Author(s):  
Nitsupa Wattanachai ◽  
Wichittra Tassaneeyakul ◽  
Andrew Rowland ◽  
David J. Elliot ◽  
Kushari Bowalgaha ◽  
...  
Keyword(s):  
Human Liver ◽  
Drug Clearance ◽  
In Vivo Extrapolation

Evaluating Lean Liver Volume as a Potential Scaler for In Vitro-In Vivo Extrapolation of Drug Clearance in Obesity Using the Model Drug Antipyrine

2020 ◽  
Vol 21 (10) ◽  
pp. 746-750
Author(s):  
Jaydeep Sinha ◽  
Stephen B. Duffull ◽  
Bruce Green ◽  
Hesham S. Al-Sallami
Keyword(s):  
Liver Volume ◽  
Drug Clearance ◽  
Liver Fat ◽  
Obese Patients ◽  
Liver Size ◽  
Total Liver Volume ◽  
Model Drug ◽  
In Vivo Extrapolation

Background : In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (>CL) involves the scaling of hepatic intrinsic clearance (CLint,uH) by functional liver size, which is approximated by total liver volume (LV) as per the convention. However, in most overweight and obese patients, LV includes abnormal liver fat, which is not thought to contribute to drug elimination, thus overestimating drug CL. Therefore, lean liver volume (LLV) might be a more appropriate scaler of CLint,uH. Objective : The objective of this work was to assess the application of LLV in CL extrapolation in overweight and obese patients (BMI >25 kg/m2) using a model drug antipyrine. Methods: Recently, a model to predict LLV from patient sex, weight, and height was developed and evaluated. In order to assess the LLV model’s use in IVIVE, a correlation-based analysis was conducted using antipyrine as an example drug. Results : In the overweight group (BMI >25 kg/m2), LLV could describe 36% of the variation in antipyrine CL (R2 = 0.36), which was >2-fold higher than that was explained by LV (R2 = 0.17). In the normal-weight groupjats:(BMI ≤25 kg/m2), the coefficients of determination were 58% (R2 = 0.58) and 43% (R2= 0.43) for LLV and LV, respectively. Conclusion : The analysis indicates that LLV is potentially a more appropriate descriptor of functional liver size than LV, particularly in overweight individuals. Therefore, LLV has a potential application in IVIVE of CL in obesity.

Hepatic Scaling Factors for In Vitro-In Vivo Extrapolation (IVIVE) of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis

2021 ◽  
pp. DMD-AR-2021-000359
Author(s):  
Areti-Maria Vasilogianni ◽  
Brahim Achour ◽  
Daniel Scotcher ◽  
Sheila Annie Peters ◽  
Zubida M. Al-Majdoub ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Drug Clearance ◽  
Scaling Factors ◽  
Metabolic Drug ◽  
In Vivo Extrapolation

Prediction of hepatic plasma clearance in vivo from gel-entrapped rat and human hepatocytes

2013 ◽  
Vol 91 (2) ◽  
pp. 178-186 ◽  
Author(s):  
Jian Yin ◽  
Hongxia Qiu ◽  
Jing Dai ◽  
Yanhua Lu ◽  
Rong Zhao ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Rat Hepatocytes ◽  
Drug Clearance ◽  
Human Hepatocytes ◽  
Drug Binding ◽  
Parallel Tube ◽  
Predicted Values ◽  
The Mathematical Model

This paper aimed to evaluate the applicability of gel-entrapped rat and human hepatocytes in the prediction of hepatic plasma clearance (CLh,plasma) in vivo. The in vitro intrinsic clearances (CLint,in vitro) for the selected compounds were determined from the substrate disappearance rate, and further used to predict CLh,plasma using 3 classical mathematical models (well-stirred, parallel-tube, and dispersion) and disregarding drug binding. As a result, the predicted values from gel-entrapped rat hepatocytes were mostly within 2 SE of the literature data with a high correlation coefficient (R2) of 0.88–0.91. The predicted data with human hepatocytes also fitted well with the clinical data, indicating a high accuracy in prediction of in-vivo clearance. With respect to the mathematical model for predicting CLh,plasma, the parallel-tube and dispersion models produced a better prediction than the well-stirred model, and we suggest using the parallel-tube model because it is less complex mathematically. In conclusion, gel-entrapped hepatocytes predicted the drug clearance well and seemed to be a useful tool in the process of drug discovery.

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