Drug Transport in the Kidney

Kusuhara, Hiroyuki; Sekine, Takashi; Anzai, Naohiko; Endou, Hitoshi

doi:10.1002/9781118705308.ch15

Cited by 6 publications

(1 citation statement)

References 205 publications

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“…More than 400 transporters belonging to the ATP-binding cassette (ABC) and solute carrier (SLC) families are encoded by the human genome and numerous transporters belonging to these two super-families are expressed at the basolateral membrane (BLM) and the brush-border membrane, throughout the S1–S3 segments of the proximal tubule cells. These membrane transporters facilitate the reabsorptive and secretory functions of the nephrons [4–6]. …”

Section: Introductionmentioning

confidence: 99%

Semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated renal reabsorption: pharmacokinetics of γ-hydroxybutyric acid and l-lactate in rats

Dave

Morris

2015

J Pharmacokinet Pharmacodyn

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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 (200–1000 mg/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.

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Section: Introductionmentioning

confidence: 99%