Pharmacokinetic Interaction between the Flavonoid Luteolin and γ-Hydroxybutyrate in Rats: Potential Involvement of Monocarboxylate Transporters

Wang

Cui

et al. 2010

AAPS J

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Abstract. γ-Hydroxybutyric acid (GHB), a drug of abuse, exhibits saturable renal clearance and capacitylimited 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 (K m,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.

Section: Discussionsupporting

confidence: 85%

“…The AUC decreased with increasing R, while the dose-averaged renal clearance increased, independent of the inhibition mechanism employed. This decrease in GHB plasma concentration and AUC correlates with the pharmacological effects of GHB, as demonstrated previously (23,25,30).…”

Section: Simulation Of Inhibition Of Renal Reabsorptionsupporting

confidence: 85%

Mechanistic Toxicokinetic Model for γ-Hydroxybutyric Acid: Inhibition of Active Renal Reabsorption as a Potential Therapeutic Strategy

Wang

Cui

et al. 2010

AAPS J

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“…Both compartmental and more physiologically based models of active tubular secretion and reabsorption have been utilized in the literature. Two additional models of renal reabsorption have been described in the literature (20,21); however, one model has limited applicability as it treats urine as a distribution compartment and the other utilizes plasma drug concentrations to drive renal reabsorption. Therefore, these models were excluded from the present analysis.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Models Describing Active Renal Reabsorption and Secretion: A Simulation-Based Study

Dave

Morris

2012

AAPS J

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Abstract. The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis-Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CL r ) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/ R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1-1,000 mg/kg) was evaluated, and V max and K m parameter estimates were varied over a 100-fold range. Similar CL r values were predicted for reabsorption models (R1/R2) with variations in V max and K m . Tubular secretion models (S1/S2) yielded similar relationships between Michaelis-Menten parameter perturbations and CL r , but the predicted CL r values were threefold higher for model S1. For both reabsorption and secretion models, the greatest changes in CL r were observed with perturbations in V max , suggesting the need for an accurate estimate of this parameter. When intrinsic clearance was substituted for Michaelis-Menten parameters, it failed to predict similar CL r values even within the linear range. For models S1 and S2, renal secretion was predominant at low doses, whereas renal clearance was driven by fraction unbound in plasma at high doses. Simulations demonstrated the importance of Michaelis-Menten parameter estimates (especially V max ) for determining CL r . K m estimates can easily be obtained directly from in vitro studies. However, additional scaling of in vitro V max estimates using in vitro/in vivo extrapolation methods are required to incorporate these parameters into pharmacokinetic models.

“…The observed nonlinearity results from capacity-limited metabolism (Lettieri and Fung, 1979;Ferrara et al, 1992;Palatini et al, 1993), transporter-mediated and saturable absorption (Arena and Fung, 1980), and renal reabsorption (Morris et al, 2005). At high doses, the decreased clearance of GHB results in sustained high plasma GHB concentrations and a corresponding increase in sedative/hypnotic effect as measured by loss of righting reflex (LRR) and return to righting reflex (RRR) (Raybon and Boje, 2007;Wang et al, 2008b). Reductions in GHB sedative/hypnotic effect have been observed after the coadministration of L-lactate (Wang et al, 2008a) or luteolin (Wang et al, 2008b).…”

mentioning

confidence: 99%

“…At high doses, the decreased clearance of GHB results in sustained high plasma GHB concentrations and a corresponding increase in sedative/hypnotic effect as measured by loss of righting reflex (LRR) and return to righting reflex (RRR) (Raybon and Boje, 2007;Wang et al, 2008b). Reductions in GHB sedative/hypnotic effect have been observed after the coadministration of L-lactate (Wang et al, 2008a) or luteolin (Wang et al, 2008b). These compounds increase the renal clearance of GHB by inhibiting active renal reabsorption, mediated by monocarboxylate transporters (MCTs), resulting in a concomitant decrease in plasma concentrations.…”

mentioning

confidence: 99%

Concentration-Effect Relationships for the Drug of Abuse γ-Hydroxybutyric Acid

Roiko²,

Morse³

et al. 2010

J Pharmacol Exp Ther

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␥-Hydroxybutyric acid (GHB) is an endogenous neurotransmitter that is abused because of its sedative/hypnotic and euphoric effects. The objectives of this study were to evaluate the concentration-effect relationships of GHB in plasma, cerebrospinal fluid (CSF), brain (whole and discrete brain regions), and brain frontal cortex extracellular fluid. This information is crucial for future studies to evaluate effects of therapeutic interventions on the toxicodynamics of GHB. GHB (200 -1000 mg/kg) was administered intravenously to rats, and plasma and frontal cortex microdialysate samples were collected for up to 6 h after the dose, or plasma, CSF, and brain (whole, frontal cortex, striatum, and hippocampus) concentrations were determined at the offset of its sedative/hypnotic effect [return to righting reflex (RRR)]. GHB-induced changes in the brain neurotransmitters ␥-aminobutyric acid (GABA) and glutamate were also determined. GHB, GABA, and glutamate concentrations were measured by liquid chromatography/tandem mass spectrometry. GHB-induced sleep time significantly increased in a dosedependent manner (20-fold increase from 200 to 1000 mg/kg). GHB concentrations in plasma (300 -400 g/ml), whole brain (70 g/g), discrete brain regions (80 -100 g/g), and brain microdialysate (29 -39 g/ml) correlated with RRR. In contrast, CSF GHB and GABA and glutamate concentrations in discrete brain regions exhibited no relationship with RRR. Our results suggest that GHB-induced sedative/hypnotic effects are mediated directly by GHB and that at high GHB doses, GABA formation from GHB may not contribute to the observed sedative/hypnotic effect. These results support the use of a clinical GHB detoxification strategy aimed at decreasing plasma and brain GHB concentrations after GHB overdoses.