Precisely adjusting the hepatic clearance of highly extracted drugs using the modified well-stirred model

• Published in: Biomedicine & pharmacotherapy Vol. 141; p. 111855
• Main Authors: Hsu, Shu-Hao, Cheng, An-Chun, Chang, Tien-Yu, Pao, Li-Heng, Hsiong, Cheng-Huei, Wang, Hong-Jaan
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2021; Elsevier
• Subjects: Albumins - metabolism; Algorithms; Animals; Dialysis; Diazepam; Diazepam - blood; Diazepam - pharmacokinetics; Hepatic clearance; Humans; In vitro to in vivo extrapolation; Liver - metabolism; Male; Metabolic Clearance Rate; Models, Theoretical; Modified well-stirred model; Perfusion; Pharmaceutical Preparations - metabolism; Rats; Rats, Sprague-Dawley; Well-stirred model; FH; IPRL; Modified well-stirred model; IVIVE; Hepatic clearance; PTM; DM; DN; Cout; fu; CH,ss,u; CH,ss; HSA; QH; fu,E; Diazepam; MWSM; CH; Cin; Well-stirred model; In vitro to in vivo extrapolation; WSM; CH,u; CLint; CPTM; ERH; CLH
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.111855

Hepatic clearance has been widely studied for over 50 yr. Many models have been developed using either theoretical or empirical tests to predict drug metabolism. The well-stirred, parallel-tube, and dispersion metabolic models have been extensively discussed. However, to our knowledge, these models cannot fully describe all relevant scenarios in hepatic clearance. We addressed this issue using the isolated perfused rat liver technique with minor modifications. Diazepam was selected to illustrate different levels of drug plasma-protein binding by changing the added concentration of human serum albumin. The free fractions of diazepam at different albumin concentrations were assayed by rapid equilibrium dialysis. The experimental data provide new insights concerning an accepted formula used to describe hepatic clearance. Regarding drug concentrations passing through the liver, the driving force concentration (CH,ss) in terms of Cin (influx in the liver) or Cout (efflux from the liver) needs to be carefully considered when determining drug hepatic and intrinsic clearances. The newly established model, termed the modified well-stirred model, which was derived from the original formula, successfully estimated hepatic drug metabolism. Using the modified well-stirred model, a theoretical driving force concentration of diazepam passing through the liver was evaluated. The model was further used to assess the predictability of in vitro to in vivo extrapolation. This study was not intended to refute the existing models, but rather to augment them using experimental data. The results stress the importance of proper calculation of dose when the drug clearance deviates from the prediction of the well-stirred model. [Display omitted] •The drug availability is known to deviate from the prediction of hepatic clearance as the level of unbound drug increases.•We derived a new model from the well-stirred model to interpret the actual drug concentration driving drug elimination.•Our modified model explains the reasons for the underestimation of clearance from IVIVE and expands options to the clinic.