ORCID Profile
0000-0001-8809-1960
Current Organisation
Certara UK Ltd.
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Publisher: Wiley
Date: 02-06-2022
DOI: 10.1002/CPT.2614
Abstract: Nonalcoholic fatty liver disease (NAFLD), representing a clinical spectrum ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), is rapidly evolving into a global pandemic. Patients with NAFLD are burdened with high rates of metabolic syndrome‐related comorbidities resulting in polypharmacy. Therefore, it is crucial to gain a better understanding of NAFLD‐mediated changes in drug disposition and efficacy/toxicity. Despite extensive clinical pharmacokinetic data in cirrhosis, current knowledge concerning pharmacokinetic alterations in NAFLD, particularly at different stages of disease progression, is relatively limited. In vitro ‐to‐ in vivo extrapolation coupled with physiologically based pharmacokinetic and pharmacodynamic (IVIVE‐PBPK/PD) modeling offers a promising approach for optimizing pharmacologic predictions while refining and reducing clinical studies in this population. Use of IVIVE‐PBPK to predict intra‐organ drug concentrations at pharmacologically relevant sites of action is particularly advantageous when it can be linked to pharmacodynamic effects. Quantitative systems pharmacology/toxicology (QSP/QST) modeling can be used to translate pharmacokinetic and pharmacodynamic data from PBPK/PD models into clinically relevant predictions of drug response and toxicity. In this review, a detailed summary of NAFLD‐mediated alterations in human physiology relevant to drug absorption, distribution, metabolism, and excretion (ADME) is provided. The application of literature‐derived physiologic parameters and ADME‐associated protein abundance data to inform virtual NAFLD population development and facilitate PBPK/PD, QSP, and QST predictions is discussed along with current limitations of these methodologies and knowledge gaps. The proposed methodologic framework offers great potential for meaningful prediction of pharmacological outcomes in patients with NAFLD and can inform both drug development and clinical practice for this population.
Publisher: MDPI AG
Date: 24-04-2020
DOI: 10.3390/PHARMACEUTICS12040390
Abstract: Ac rosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral ac rosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing ac rosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of ac rosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of ac rosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of SLC22A6) and OAT3 (gene product of SLC22A8) expressing cell lines to investigate whether ac rosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with SLC22A6 or SLC22A8. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Ac rosate inhibited OAT1-mediated p-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with ac rosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by ac rosate and cellular uptake studies showed that ac rosate is a substrate for OAT1 with a Km-value of approximately 700 µM. Probenecid inhibited OAT1-mediated ac rosate uptake with a Ki-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, ac rosate was identified as a substrate of OAT1 but not OAT3.
Publisher: Wiley
Date: 25-02-2016
DOI: 10.1111/BCP.12878
Publisher: American Chemical Society (ACS)
Date: 27-09-2019
DOI: 10.1021/ACS.MOLPHARMACEUT.9B00733
Abstract: In drug development, estimating fraction absorbed (
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sibylle Neuhoff.