Physicochemical determinants of human renal clearance.
Kidney plays an important role in the elimination of drugs, especially with low or negligible hepatic clearance. An analysis of the interrelation of physicochemical properties and the human renal clearance for a data set of 391 drugs or compounds tested in humans is presented. The data set indicated that lipophilicity shows a negative relationship while polar descriptors show a positive relationship with renal clearance. Analysis of net secreted and net reabsorbed subsets revealed that hydrophilic ionized compounds are probable compounds to show net secretion and a possible drug-drug interaction due to their likely interaction with uptake transporters and inherent low passive reabsorption. The physicochemical space and renal clearance were also statistically analyzed by therapeutic area. In conclusion, ionization state, lipophilicity, and polar descriptors are found to be the physicochemical determinants of renal clearance. These fundamental properties can be valuable in early prediction of human renal clearance and can aid the chemist in structural modifications to optimize drug disposition.
Varma
Manthena V S
MV
Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA. manthena.v.varma@pfizer.com
Feng
Bo
B
Obach
R Scott
RS
Troutman
Matthew D
MD
Chupka
Jonathan
J
Miller
Howard R
HR
El-Kattan
Ayman
A
D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007668:Kidney / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008970:Molecular Weight