Renal clearance in drug discovery and development: molecular descriptors, drug transporters and disease state.
BACKGROUND
Kidney plays a key role in the elimination of xenobiotics and metabolic products from the body, where renal clearance is determined by glomerular filtration, tubular secretion and reabsorption processes. The proximal tubule of the nephron is equipped with multi-specificity uptake and efflux transporters for the secretion of a broad range of xenobiotics, while the compound physicochemical space drives the tubular reabsorption. Due to involvement of transporters, renal clearance is possibly associated with renal drug-drug interactions (DDIs) in clinical situations. Nevertheless, renal insufficiency in diseased population is associated with altered transporter activity and evidently affects the pharmacokinetics of both renally and non-renally cleared compounds. Thus, early information on renal clearance is critical for successful development of compounds in certain chemical space.


METHODS
This review provides updated information on the influence of physicochemical properties and the relevance of transporters in renal clearance and the associated drug interactions. In silico tools to predict the renal clearance at the discovery stage along with the potential alterations in drug disposition in the renal disease state are discussed with preclinical and clinical examples.


RESULTS
The review provides comprehensive knowledge with recent examples to moderate renal disposition concerns in the drug discovery and development settings.


CONCLUSIONS
Consideration of clearance pathways early in the discovery process has become critical for successful development of compounds. Although significant progress has been made in elucidating the physicochemical drivers and biochemical processes for this pathway, the predictive ability remains a challenge. Furthermore, development of renally cleared compounds should progress with a clear understanding of possible issues including transporter-mediated DDI and disease state.
Feng
Bo
B
Departments of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Groton, CT 06340, USA.
LaPerle
Jennnifer L
JL
Chang
George
G
Varma
Manthena V S
MV
D000818:Animals; D001692:Biological Transport; D002986:Clinical Trials as Topic; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004364:Pharmaceutical Preparations