Protein Binding and Hepatic Clearance: Re-Examining the Discrimination between Models of Hepatic Clearance with Diazepam in the Isolated Perfused Rat Liver Preparation

Wang, Hong-Jaan; Benet, Leslie Z.

doi:10.1124/dmd.119.088872

Cited by 9 publications

(16 citation statements)

References 17 publications

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“…In study of G. H. El-Sokkary (2008) [40] rats were watered a dose of diazepam of 5 mg / kg body weight and this was characterized as a high dose. Rat liver often cannot metabolize the entire amount of the applied diazepam and thus accumulates it [41]. In our study, there was an increased liver neovascularisation after diazepam treatment, which was confi rmed by an increase in the volume density of capillary sinus in the liver tissue.…”

Section: Discussionsupporting

confidence: 59%

Effects of Diazepam on Hematological and Histological Parameters in Rats / in Vivo and Unbiased Stereological Investigation

et al. 2022

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Diazepam-based drugs are widely used today in human treatment. Diazepam may be a primary drug aimed at treating neurological diseases or an associated drug in the treatment of other diseases in the purpose of symptomatic therapy. The sedative effect of diazepam characterizes it as a drug that people usually use on their own and without a doctor’s supervision. Directly, but also through influencing the nervous system, diazepam disrupts proper functioning of all body organs. The purpose of this paper was to examine the effects of diazepam on blood and cytohistological parameters of rats in an in vivo experiment. Mallory-Azan and immunochistochemical staining methods BLX-CX and Survivin tissues of liver, kidney and spleen of rats were used to achieve the set goal. Cytometric analysis of rats detected cells in apoptosis and measurements of stereological parameters were made using a system according to Cavalier’s principle. Results of analysis of hematological and histological parameters indicate a detrimental effect of diazepam on blood parameters, as well as on structure and functioning of the liver, kidneys and spleen of rats. This paper is a foundation for further detailed scientific research with the aim of elucidating all harmful effects that diazepam has on all organs in the body of rats. This data could serve as a starting point for future studies in clinical pharmacology on therapeutic protocols for usage of diazepam-based sedatives.

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Section: Discussionsupporting

confidence: 59%

Effects of Diazepam on Hematological and Histological Parameters in Rats / in Vivo and Unbiased Stereological Investigation

et al. 2022

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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%

“…where C is the total diazepam concentration used for equilibrium dialysis; C=1 µg/ml=3.512 µM in both experiments (Wang and Benet, 2019;Hsu et al, 2021).…”

Section: Methodsmentioning

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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Blood Flow Distribution and Membrane Transporters as Determinant Factors of Tissue Drug Concentration

Fagiolino,

Talevi,

Vázquez

et al. 2024

ADME Processes in Pharmaceutical Sciences

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Protein Binding and Hepatic Clearance: Re-Examining the Discrimination between Models of Hepatic Clearance with Diazepam in the Isolated Perfused Rat Liver Preparation

Cited by 9 publications

References 17 publications

Effects of Diazepam on Hematological and Histological Parameters in Rats / in Vivo and Unbiased Stereological Investigation

Effects of Diazepam on Hematological and Histological Parameters in Rats / in Vivo and Unbiased Stereological Investigation

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

Blood Flow Distribution and Membrane Transporters as Determinant Factors of Tissue Drug Concentration

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