Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy
Journal Title: The AAPS Journal - Year 2010, Vol 12, Issue 3
Abstract
γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacity-limited metabolism. The objectives of this study were to construct a mechanistic toxicokinetic (TK) model describing saturable renal reabsorption and capacity-limited metabolism of GHB and to predict the effects of inhibition of renal reabsorption on GHB TK in the plasma and urine. GHB was administered by iv bolus (200–1,000 mg/kg) to male Sprague-Dawley rats and plasma and urine samples were collected for up to 6 h post-dose. GHB concentrations were determined by LC/MS/MS. GHB plasma concentration and urinary excretion were well-described by a TK model incorporating plasma and kidney compartments, along with two tissue and two ultrafiltrate compartments. The estimate of the Michaelis-Menten constant for renal reabsorption (Km,R) was 0.46 mg/ml which is consistent with in vitro estimates of monocarboxylate transporter (MCT)-mediated uptake of GHB (0.48 mg/ml). Simulation studies assessing inhibition of renal reabsorption of GHB demonstrated increased time-averaged renal clearance and GHB plasma AUC, independent of the inhibition mechanism assessed. Co-administration of GHB (600 mg/kg iv) and l -lactate (330 mg/kg iv bolus plus 121 mg/kg/h iv infusion), a known inhibitor of MCTs, resulted in a significant decrease in GHB plasma AUC and an increase in time-averaged renal clearance, consistent with the model simulations. These results suggest that inhibition of renal reabsorption of GHB is a viable therapeutic strategy for the treatment of GHB overdoses. Furthermore, the mechanistic TK model provides a useful in silico tool for the evaluation of potential therapeutic strategies.
Authors and Affiliations
Melanie A. Felmlee, Qi Wang, Dapeng Cui, Samuel A. Roiko, Marilyn E. Morris
Keywords
Related Articles
- EP ID EP681391
- DOI 10.1208/s12248-010-9197-x
- Views 56
- Downloads 0
Co-Delivery of Autoantigen and B7 Pathway Modulators Suppresses Experimental Autoimmune Encephalomyelitis
The online version of this article (doi:10.1208/s12248-014-9671-y) contains supplementary material, which is available to authorized users.
Modelling and PBPK Simulation in Drug Discovery
Physiologically based pharmacokinetic (PBPK) models are composed of a series of differential equations and have been implemented in a number of commercial software packages. These models require species-specific and comp...
Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products
Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other...
Peptide Developability at the Discovery-to-Development Interface—Current State and Future Opportunities
Modeling Testosterone Circadian Rhythm in Hypogonadal Males: Effect of Age and Circannual Variations
The objective of this study was to characterize the baseline circadian rhythm of testosterone levels in hypogonadal men. A total of 859 baseline profiles of testosterone from hypogonadal men were included in this analysi...