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

Hsu, S. C.; Cheng, Anchun; Chang, Tien-Yu; Pao, Li-Heng; Hsiong, Cheng-Huei; Wang, Hong-Jaan

doi:10.1016/j.biopha.2021.111855

Cited by 6 publications

(17 citation statements)

References 30 publications

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“…IPRL and equilibrium dialysis data, initially published by Wang and Benet at the University of California San Francisco, USA (Wang and Benet, 2019), and Hsu et al at the National Defense Medical Center, Taipei, Taiwan (Hsu et al, 2021), were analyzed to evaluate the impact of saturable plasma protein binding on hepatic clearance model discrimination. The original data and key experimental parameters are summarized in TableS1.…”

Section: Methodsmentioning

confidence: 99%

“…The saturable unbound fraction (f u,sat ) is determined by the maximal binding capacity (B max ), protein binding dissociation constant (K D ), and non-saturable binding constant or binding potential (K nsb ). These parameters were estimated from the plasma protein binding data (Wang and Benet, 2019;Hsu et al, 2021) with Eq.7 using GraphPad Prism 9.1.0 with 1/X 2 weighting (GraphPad Software, San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…However, the MWSM does not follow the common assumption that CL int,u,MWSM is independent of Q H (Hsu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, an additional fourth model of hepatic clearance was introduced, the modified wellstirred model (MWSM; Eq.4; (Hsu et al, 2021)).…”

Section: Introductionmentioning

confidence: 99%

“…To test the effect of saturable plasma protein binding on hepatic clearance model discrimination, we explored a high-quality IPRL dataset comparing diazepam clearance at different human serum albumin (HSA) concentrations (Wang and Benet, 2019;Hsu et al, 2021). While there is data available on many experimental models and drugs, we chose diazepam for our case study as this IPRL dataset provided the richest data source for albumin-related changes in CL H .…”

Section: Introductionmentioning

confidence: 99%

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Assumptions Underlying Hepatic Clearance Models: Recognizing the Influence of Saturable Protein Binding on Driving Force Concentration and Discrimination Between Models of Hepatic Clearance

et al. 2023

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One underlying assumption of hepatic clearance models is often underappreciated. Namely, plasma protein binding is assumed to be non-saturable within a given drug concentration range, dependent only on protein concentration and K D . However, in vitro hepatic clearance experiments often use low albumin concentrations that may be prone to saturation effects, especially for high-clearance compounds, where the drug concentration changes rapidly.Diazepam isolated perfused rat liver literature datasets collected at varying concentrations of albumin were used to evaluate the predictive utility of four hepatic clearance models (the wellstirred, parallel tube, dispersion, and modified well-stirred model) while both ignoring and accounting for potential impact of saturable protein binding on hepatic clearance model discrimination. In agreement with previous literature findings, analyses without accounting for saturable binding showed poor clearance prediction using all four hepatic clearance models.Here, we show that accounting for saturable albumin binding improves clearance predictions across the four hepatic clearance models. Additionally, the well-stirred model best reconciles the difference between the predicted and observed clearance data, suggesting that the wellstirred model is an appropriate model to describe diazepam hepatic clearance when considering appropriate binding models.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…However, the MWSM does not follow the common assumption that CL int,u,MWSM is independent of Q H (Hsu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, an additional fourth model of hepatic clearance was introduced, the modified wellstirred model (MWSM; Eq.4; (Hsu et al, 2021)).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning