Effects of L-lactate and D-mannitol on gamma-hydroxybutyrate toxicokinetics and toxicodynamics in rats

Abstract

Overdoses of gamma-hydroxybutyrate (GHB), a drug of abuse, result in coma, respiratory arrest, and death. The objective of this study was to evaluate a potential GHB detoxification strategy by inhibiting the monocarboxylate transporter (MCT)-mediated renal reabsorption of GHB in rats, using the MCT substrate L-lactate. The use of the osmotic diuretic D-mannitol alone or combined with L-lactate was also explored. GHB (208 mg/h/kg) was infused i.v. for 3 h in the absence or presence of L-lactate (60.5, 121, and 302.5 mg h(-1) kg(-1)), D-mannitol (0.5 g/kg), or L-lactate (60.5 mg h(-1) kg(-1)) combined with D-mannitol (0.5 g/kg). GHB in plasma and urine samples was determined along with blood pH, electrolytes, glucose, and L-lactate. Administration of L-lactate, or the combination of L-lactate and D-mannitol, but not D-mannitol alone, significantly increased the renal and total clearances of GHB in rats. Blood pH and electrolyte concentrations exhibited small changes with GHB, GHB/lactate, and GHB/mannitol treatments, although most values remained within their normal range. The concomitant administration of lactated Ringer's solution (28 mM L-lactate) at 300 mul/min with mannitol (0.5 g/kg) resulted in a significant increase in GHB clearance and a decrease in sleep time after an i.v. dose of 1 g/kg. Overall, our results indicated the following: 1) the use of the MCT inhibitor L-lactate can increase the renal and total clearances of GHB, and 2) the combination of lactated Ringer's solution and D-mannitol significantly alters GHB toxicokinetics and toxicodynamics and represents a potential clinical detoxification strategy for the treatment of GHB overdoses.

Fig. 1

The renal clearance (CL _R), metabolic clearance (CL_m), and total clearance (CL_T) of GHB determined after the infusion of different doses of L-lactate. The control was administered GHB (208 mg/kg/h) alone. L-Lactate-1, L-lactate-2, and L-lactate-3 represent the doses of 60.5, 121, and 302.5 mg h⁻¹ kg⁻¹, respectively. Results are plotted as mean ± S.D., n = 3 to 5. Statistical differences were compared with the control (**, p < 0.01; ***, p < 0.001), using a one-way ANOVA followed by a Dunnett's post hoc test.

Fig. 2

The renal clearance (CL_R), metabolic clearance (CL_m), and total clearance (CL_T) of GHB determined after the concomitant treatment with D-mannitol, L-lactate, or D-mannitol/L-lactate. The control was administered with GHB (208 mg h−1 kg⁻¹) only. L-Lactate was administered at a dose of 60.5 mg h⁻¹ kg⁻¹ by i.v. infusion, D-mannitol was administered as an i.v. bolus dose of 0.5 g/kg, and Man + Lact represents the combined treatment with D-mannitol and L-lactate. One-way ANOVA followed by Dunnett's test, n = 3-8, mean ± S.D. **, p < 0.01.

Fig. 3

Effect of treatment with GHB alone or GHB with L-lactate, GHB with D-mannitol, or GHB with the combination of D-mannitol/L-lactate on urine pH and volume. Urine pH changes (A) and urine volume changes (B) after administration of 60.5 mg h⁻¹ kg⁻¹ L-lactate, 0.5 g/kg D-mannitol, and the combination of D-mannitol and L-lactate. One-way ANOVA followed by Dunnett's test, n = 3 to 5, mean ± S.D. *, p < 0.05; **, p < 0.01.

Fig. 4

Plasma concentrations of GHB after treatment with GHB alone or with concomitant lactated Ringer's solution, D-mannitol, or lactated Ringer's solution/D-mannitol administration. The control was administered GHB (1000 mg/kg, i.v. bolus) only, followed by i.v. infusion of saline at the rate of 300 µl/min; L-lactate represents the i.v. infusion of lactated Ringer's solution at the rate of 300 µl/min; D-mannitol represents the 0.5g/kg bolus dose of D-mannitol; and Man + Lact represents the combined treatment with D-mannitol 0.5g/kg and i.v. infusion of lactated Ringer's solution at the rate of 300 µl/min, n = 3 to 4 per group.