Impact of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) on the expression and function of hepatobiliary transporters: A comprehensive mechanistic review.

The liver plays a central role in the biotransformation and disposition of endogenous molecules and xenobiotics. In addition to drug-metabolizing enzymes, transporter proteins are key determinants of drug hepatic clearance. Hepatic transporters are transmembrane proteins that facilitate the movement of chemicals between sinusoidal blood and hepatocytes. Other drug transporters translocate molecules from hepatocytes into bile canaliculi for biliary excretion. The formers are known as basolateral, while the latter are known as canalicular transporters. Also, these transporters are classified into two super-families, the solute carrier transporter (SLC) and the adenosine triphosphate (ATP)-binding cassette (ABC) transporter. The expression and function of transporters involve complex regulatory mechanisms, which are contributing factors to interindividual variability in drug pharmacokinetics and disposition. A considerable number of liver diseases are known to alter the expression and function of drug transporters. Among them, non-alcoholic fatty liver disease (NAFLD) is a chronic condition with a rapidly increasing incidence worldwide. NAFLD, recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), is a disease continuum that includes steatosis with or without mild inflammation (NASH), and potentially neuroinflammatory pathology. NASH is additionally characterized by the presence of hepatocellular injury. During NAFLD and NASH, drug transporters exhibit altered expression and function, leading to altered drug pharmacokinetics and pharmacodynamics, thus increasing the risk of adverse drug reactions. The purpose of the present review is to provide comprehensive mechanistic information on the expression and function of hepatic transporters under fatty liver conditions and hence, the impact on the pharmacokinetic profiles of certain drugs from the available pre-clinical and clinical literature.

Nonclinical pharmacokinetics and biodistribution of VSV-GP using methods to decouple input drug disposition and viral replication.

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice. First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors.