PT  - JOURNAL ARTICLE
AU  - Guo, Zeyu
AU  - Gao, Jingjing
AU  - Liu, Li
AU  - Liu, Xiaodong
TI  - Quantitatively Predicting Effects of Exercise on Pharmacokinetics of Drugs Using a Physiologically Based Pharmacokinetic Model
AID  - 10.1124/dmd.124.001809
DP  - 2024 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1271--1287
VI  - 52
IP  - 11
4099  - http://dmd.aspetjournals.org/content/52/11/1271.short
4100  - http://dmd.aspetjournals.org/content/52/11/1271.full
SO  - Drug Metab Dispos2024 Nov 01; 52
AB  - Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = ΣaiHRi was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5th–95th percentiles of the simulations, and the estimated peak concentrations (Cmax) and area under the curve (AUC) of drugs were also within 0.5–2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters.SIGNIFICANCE STATEMENT This study simulated real-time changes of human physiological parameters during exercise in the WB-PBPK model and comprehensively investigated pharmacokinetic changes during exercise following oral and intravenous administration. Furthermore, the factors affecting pharmacokinetics during exercise were also revealed.