Pharmacokinetics and Drug Transport Mechanisms

Pharmacokinetics examines the journey of a drug through the body, encompassing absorption, distribution, metabolism and excretion (ADME). Following administration, a compound must traverse biological barriers, often via specialised uptake transporters, to reach its site of action. Distribution is shaped by binding to plasma proteins and passage through endothelial membranes, while metabolic enzymes—most notably cytochrome P450 oxidases and conjugating systems such as UDP-glucuronosyltransferases—modify xenobiotics to more polar forms. Excretion pathways involve renal secretion, biliary elimination and, increasingly recognised, gut-liver crosstalk mediated by transporters. Drug transport proteins, including organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs) and multidrug efflux pumps (P-glycoprotein, BCRP), govern intracellular concentrations and underpin interindividual variability. Physiologically based pharmacokinetic (PBPK) modelling integrates in vitro data and human physiology to predict concentration–time profiles and anticipate drug–drug interactions. Advances in structural biology, in vitro systems and endogenous biomarkers are refining our ability to forecast clinical outcomes, tailor therapy to genetic backgrounds and mitigate adverse events. A mechanistic understanding of transporter–enzyme interplay is therefore essential to optimise dosing regimens, support regulatory decisions and advance precision medicine.

Research from Nature Portfolio

Recent studies have employed cryo-electron microscopy to resolve the high-resolution structures of two key hepatic uptake transporters, revealing ligand-binding sites and conformational states. One work elucidated the atomic details of organic anion transporting polypeptide 1B1 and its close homologue 1B3 in outward- and inward-open forms, rationalising substrate specificity and providing a structural basis for in silico docking of statins. This advance informs prediction of transporter-mediated drug–drug interactions and enables rational design of compounds with reduced clearance liabilities.

Investigations into renal organic anion transporters have highlighted the in vivo roles of OAT1 and OAT3 in handling endogenous and microbiome-derived toxins. Knock-out models demonstrated that these transporters coordinate the excretion of over 35 solutes implicated in uremic syndrome and interorgan communication. This work supports a remote sensing and signalling framework, emphasising transporter networks in systemic homeostasis and offering insights into chronic kidney disease pharmacotherapy.

Pharmacokinetics and Drug Transport Mechanisms publication trend

The graph below shows the total number of articles in pharmacokinetics and drug transport mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Pharmacokinetics: The study of drug absorption, distribution, metabolism and excretion over time.

ADME: Acronym for absorption, distribution, metabolism and excretion, the four key processes determining drug fate.

Organic Anion Transporting Polypeptide (OATP): A family of membrane transporters that mediate the hepatic uptake of diverse anionic compounds, including drugs.

Cytochrome P450: A superfamily of oxidase enzymes that catalyse phase I metabolism, often initiating drug biotransformation.

Physiologically Based Pharmacokinetic (PBPK) Modelling: A computational approach that uses physiological parameters and drug properties to simulate concentration–time profiles in humans.

References

1. Cryo-EM structures of human organic anion transporting polypeptide OATP1B1. Cell Research (2023).
2. Structure of human drug transporters OATP1B1 and OATP1B3. Nature Communications (2023).
3. Inhibition and induction of CYP enzymes in humans: an update. Archives of Toxicology (2020).
4. Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes. Scientific Reports (2017).
5. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions. European Journal of Pharmaceutical Sciences (2016).
6. Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B‐Mediated Drug–Drug Interactions Using Population Pharmacokinetic Modeling and Simulation. Clinical Pharmacology & Therapeutics (2018).