Cirrhosis, a chronic liver disease, alters hepatic drug disposition; however, little is known about micromechanisms underpinning disease progression and how they contribute to changes in liver disposition properties. In this article, the authors present multilevel, agent-based and agent-directed In Silico Livers (ISLs) to probe plausible micro-mechanistic details for a cationic drug, diltiazem,...

OBJECTIVE Aspirin administered orally is one of most widely self-prescribed drugs to treat headaches or other pains. The aim of this study was to evaluate whether the influence of different beverages may be used to help in the ingestion of an aspirin tablet on the pharmacokinetic parameters of this drug. METHOD This study was undertaken in five healthy volunteers. Seven beverages were tested:...

Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatme...

Pharmacokinetic interactions, e.g. modulation of drug transporters like P-glycoprotein at the blood-brain barrier, can be a reason for treatment non-response. This study focuses on the influence of induction of drug transporters on the disposition of the antipsychotic drugs risperidone and 9-hydroxyrisperidone. Brain and serum concentrations of risperidone and its active metabolite 9-hydroxyris...

Functional interplay between transporters and drug-metabolizing enzymes is currently one of the hottest topics in the field of drug metabolism and pharmacokinetics. Uptake transporter-enzyme interplay is important to determine intrinsic hepatic clearance based on the extended clearance concept. Enzyme-efflux transporter interplay, which includes both sinusoidal (basolateral) and canalicular eff...

Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized bac...