Physiologically Based Pharmacokinetic Modeling of Bosentan Identifies the Saturable Hepatic Uptake As a Major Contributor to Its Nonlinear Pharmacokinetics

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Masanobu SatoYuichi Sugiyama

Abstract

Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, P450-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its intravenous administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters, and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism, or both were compared. The prediction from the bottom-up approach (models 1 and 2) yielded blood bosentan concentration-time profiles and their systemic clearance values that were not in good agreement with the clinically observed data. From top-down approaches (models 3, 4, 5-1, and 5...Continue Reading

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May 5, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takashi YoshikadoYuichi Sugiyama

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Citations

Apr 11, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Qingcheng MaoJoanne Wang
Dec 12, 2019·Pharmaceutical Research·Anke-Katrin VolzThorsten Lehr
Jun 20, 2019·The AAPS Journal·Andrea TreyerPer Artursson
Sep 25, 2020·Clinical Pharmacology and Therapeutics·Christine WeglerPer Artursson

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