Application of physiologically based (PBK) modeling to quantify the effect of the antibiotic tobramycin on bile acid levels in human plasma.

Systemic bile acid homeostasis plays an important role in human health. In this study, a physiologically based kinetic (PBK) model that includes microbial bile acid deconjugation and intestinal bile acid reuptake via the apical sodium-dependent bile acid transporter (ASBT) was applied to predict the systemic plasma bile acid concentrations in human upon oral treatment with the antibiotic tobramycin. Tobramycin was previously shown to inhibit intestinal deconjugation and reuptake of bile acids and to affect bile acid homeostasis upon oral exposure of rats.

From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based kinetic modeling.

Cholestasis is characterized by hepatic accumulation of bile acids. Clinical manifestation of cholestasis only occurs in a small proportion of exposed individuals. The present study aims to develop a new approach methodology (NAM) to predict drug-induced cholestasis as a result of drug-induced hepatic bile acid efflux inhibition and the resulting bile acid accumulation.

Intestinal in vitro transport assay combined with physiologically based kinetic modeling as a tool to predict bile acid levels in vivo.

Bile acid homeostasis is vital for numerous metabolic and immune functions in humans. The enterohepatic circulation of bile acids is extremely efficient, with ~95% of intestinal bile acids being reabsorbed. Disturbing intestinal bile acid uptake is expected to substantially affect intestinal and systemic bile acid levels.

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis.

Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop physiologically based kinetic (PBK) models that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor.

Hepatic bile acid synthesis and secretion: Comparison of in vitro methods.

Reliable hepatic in vitro systems are crucial for the safety assessment of xenobiotics. Certain xenobiotics decrease the hepatic bile efflux, which can ultimately result in cholestasis. Preclinical animal models and the currently available in vitro systems poorly predict a xenobiotic's cholestatic potential.