caa a22 4500 605534136 CHVBK 20210128100841.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s10928-015-9441-1 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9441-1 Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l -lactate in rats [Elektronische Daten] [Rutwij Dave, Marilyn Morris] This study developed a semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated active reabsorption. The model was applied to data for the drug of abuse γ-hydroxybutyric acid (GHB), which exhibits monocarboxylate transporter (MCT1/SMCT1)-mediated renal reabsorption. The kidney model consists of various nephron segments—proximal tubules, Loop-of-Henle, distal tubules, and collecting ducts—where the segmental fluid flow rates, volumes, and sequential reabsorption were incorporated as functions of the glomerular filtration rate. The active renal reabsorption was modeled as vectorial transport across proximal tubule cells. In addition, the model included physiological blood, liver, and remainder compartments. The population pharmacokinetic modeling was performed using ADAPT5 for GHB blood concentration-time data and cumulative amount excreted unchanged into urine data (200-1000mg/kg IV bolus doses) from rats [Felmlee et al (PMID: 20461486)]. Simulations assessed the effects of inhibition (R=[I]/KI=0-100) of renal reabsorption on systemic exposure (AUC) and renal clearance of GHB. Visual predictive checks and other model diagnostic plots indicated that the model reasonably captured GHB concentrations. Simulations demonstrated that the inhibition of renal reabsorption significantly increased GHB renal clearance and decreased AUC. Model validation was performed using a separate dataset. Furthermore, our model successfully evaluated the pharmacokinetics of l-lactate using data obtained from Morse et al (PMID: 24854892). In conclusion, we developed a semi-mechanistic kidney model that can be used to evaluate transporter-mediated active renal reabsorption of drugs by the kidney. Springer Science+Business Media New York, 2015 Semi-mechanistic kidney model nationallicence Physiologically-relevant fluid reabsorption nationallicence Transporter-mediated renal reabsorption nationallicence Population pharmacokinetics nationallicence γ-Hydroxybutyric acid (GHB) nationallicence l -Lactate nationallicence Monocarboxylate transporters (MCTs) nationallicence Dave Rutwij Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA aut Morris Marilyn Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 497-513 1567-567X 42:5<497 2015 42 10928 https://doi.org/10.1007/s10928-015-9441-1 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9441-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Dave Rutwij Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA aut NATIONALLICENCE 700 1- Morris Marilyn Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/5(2015-10-01), 497-513 1567-567X 42:5<497 2015 42 10928