This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CL). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CL) rather than CL as posed. We further demonstrate how classic hepatic clearance models with an assumed CL, while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics (PK) and physiologically based pharmacokinetic (PBPK) modeling.
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http://dx.doi.org/10.1208/s12248-021-00656-z | DOI Listing |
J Clin Pharmacol
January 2025
Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
This study evaluates the impact of acute pyelonephritis in pregnant women on the in vivo activity of renal OAT3 using the endogenous biomarker (EB) 6β-hydroxycortisol (6β-OHF) renal clearance (CL 6β-OHF) and AUC validated by correlating with the secretion clearance (CL) of the probe drug furosemide. Additionally, 6β-OHF formation clearance (CL 6β-OHF) as well as urinary (Ae/Ae) and plasma (AUC/AUC) ratios were also evaluated as EB for hepatic CYP3A activity. Pregnant women in their third trimester of gestation, diagnosed with acute pyelonephritis, were recruited before (pre-treatment, n = 8) and after (post-treatment, n = 8) cefuroxime treatment and resolution of acute pyelonephritis.
View Article and Find Full Text PDFAAPS J
January 2025
Clinical Pharmacology Modeling and Simulation, Amgen, One Amgen Center Drive, Thousand Oaks, CA, 91320-0777, USA.
Sotorasib is a novel KRAS inhibitor that has shown robust efficacy, safety, and tolerability in patients with KRAS mutation. The objectives of the population pharmacokinetic (PK) analysis were to characterize sotorasib population PK in healthy subjects and patients with advanced solid tumors with KRAS mutation from 6 clinical studies, evaluate the effects of intrinsic and extrinsic factors on PK parameters, and perform simulations to further assess the impact of identified covariates on sotorasib exposures. A two-compartment disposition model with three transit compartments for absorption and time-dependent clearance and bioavailability well described sotorasib PK.
View Article and Find Full Text PDFJ Control Release
January 2025
Univ Brest, Inserm, EFS, UMR 1078, GGB, F-29200, Brest, France; CHU de Brest, Service de Génétique Médicale et de Biologie de la Reproduction, F-29200 Brest, France. Electronic address:
Aerosol delivery represents a rapid and non-invasive way to directly reach the lungs while escaping the hepatic first-pass effect. The development of pulmonary drugs for respiratory diseases such as cystic fibrosis, lung infections, pulmonary fibrosis or lung cancer requires an enhanced understanding of the relationships between the natural physiology of the respiratory system and the pathophysiology of these conditions. This knowledge is crucial to better predict and thereby control drug deposition.
View Article and Find Full Text PDFClin Pharmacokinet
January 2025
Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence.
View Article and Find Full Text PDFPLoS One
January 2025
ESQlabs Gmbh, Saterland, Germany.
Digital twins, driven by data and mathematical modelling, have emerged as powerful tools for simulating complex biological systems. In this work, we focus on modelling the clearance on a liver-on-chip as a digital twin that closely mimics the clearance functionality of the human liver. Our approach involves the creation of a compartmental physiological model of the liver using ordinary differential equations (ODEs) to estimate pharmacokinetic (PK) parameters related to on-chip liver clearance.
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