Development of a Genetically Integrated PBPK Model for Predicting Uric Acid Homeostasis in Humans

Noppavit Kaewlin, Monrudee Liangruksa, Teeraphan Laomettachit

Abstract

Serum uric acid (SUA) balance is mainly regulated by the excretion and reabsorption by the kidneys. Much attention has recently been focused on the genetic variation of renal uric acid transporter genes that affect uric acid homeostasis. Here, we have developed a system of equations to study the human uric acid homeostasis using the physiologically based pharmacokinetic (PBPK) model. The PBPK model incorporates blood flow and tissue compartment of organs to describe how uric acid is distributed within the body. We have also implemented the concept of sub-compartments within the kidneys that allows the model to integrate the genetics of individual patients. We chose to model patients with single nucleotide polymorphisms (SNPs) on the SLC2A9 gene (encoding the urate transporter protein, GLUT9) because the gene variation directly affects the amount of uric acid excreted and reabsorbed by the kidneys. Our model development results in a framework for implementing genetic values as a subsystem while giving way to a better representation of human physiology in highly complex systems.