Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l -lactate in rats
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| 024 | 7 | 0 | |a 10.1007/s10928-015-9441-1 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s10928-015-9441-1 | ||
| 245 | 0 | 0 | |a Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l -lactate in rats |h [Elektronische Daten] |c [Rutwij Dave, Marilyn Morris] |
| 520 | 3 | |a 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. | |
| 540 | |a Springer Science+Business Media New York, 2015 | ||
| 690 | 7 | |a Semi-mechanistic kidney model |2 nationallicence | |
| 690 | 7 | |a Physiologically-relevant fluid reabsorption |2 nationallicence | |
| 690 | 7 | |a Transporter-mediated renal reabsorption |2 nationallicence | |
| 690 | 7 | |a Population pharmacokinetics |2 nationallicence | |
| 690 | 7 | |a γ-Hydroxybutyric acid (GHB) |2 nationallicence | |
| 690 | 7 | |a l -Lactate |2 nationallicence | |
| 690 | 7 | |a Monocarboxylate transporters (MCTs) |2 nationallicence | |
| 700 | 1 | |a Dave |D Rutwij |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA |4 aut | |
| 700 | 1 | |a Morris |D Marilyn |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA |4 aut | |
| 773 | 0 | |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 497-513 |x 1567-567X |q 42:5<497 |1 2015 |2 42 |o 10928 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s10928-015-9441-1 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s10928-015-9441-1 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Dave |D Rutwij |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Morris |D Marilyn |u Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, 14214, Buffalo, NY, USA |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Pharmacokinetics and Pharmacodynamics |d Springer US; http://www.springer-ny.com |g 42/5(2015-10-01), 497-513 |x 1567-567X |q 42:5<497 |1 2015 |2 42 |o 10928 | ||