Pharmacokinetics of 1,4-Butanediol in Rats: Bioactivation to γ-Hydroxybutyric Acid, Interaction with Ethanol, and Oral Bioavailability
Journal Title: The AAPS Journal - Year 2008, Vol 10, Issue 1
Abstract
1,4-Butanediol (BD), a substance of abuse, is bioactivated to γ-hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcohol dehydrogenase, we hypothesized that there may also be a metabolic interaction between ethanol (ETOH) and BD. We therefore studied, in rats, the plasma PK of GHB, BD and ETOH each at two intravenous (IV) doses, when each substance was given alone, and when GHB or BD was co-administered with ETOH. Results showed that bioconversion of intravenously administered BD to GHB was complete, and that both GHB and BD exhibited nonlinear PK. Various population PK models were analyzed using NONMEM VI, and the best disposition model was found to include two PK compartments each for BD, an (unmeasured) putative semialdehyde intermediate (ALD), GHB and ETOH, the presence of nonlinear (Michaelis–Menten) elimination for each compound, and several mutual inhibition processes. The most prominent mutual metabolic inhibition was found between ETOH and BD, while that between GHB and ETOH was not significant. In vitro studies using liver homogenates confirmed mutual metabolic inhibitions between GHB and BD. Oral absorption of BD was best described by a first-order process with lag-time and pre-systemic metabolism from BD to ALD. Oral absorption of BD (as BD plus ALD) was rapid and complete. The fraction of the absorbed dose entering the central compartment as BD was 30% for the 1.58 mmol/kg dose and 55% for the 6.34 mmol/kg dose. At 6.34 mmol/kg IV, the onset of loss of righting reflex (LRR) for BD was significantly delayed vs. that produced by GHB (72.0 ± 9.1 min vs. 6.7 ± 0.6 min, respectively, p < 0.001), and the total duration of LRR was prolonged for BD vs. GHB (192 ± 28 min vs. 117 ± 2 min, respectively, p < 0.05). Relative to IV dosing, oral BD produced similar but more variable LRR effects. These results may provide a quantitative PK framework for the understanding of the toxicokinetics and toxicodynamics of both BD and GHB.
Authors and Affiliations
Ho-Leung Fung, Pei-Suen Tsou, Jurgen B. Bulitta, Doanh C. Tran, Nathaniel A. Page, David Soda, Sun Mi Fung
Keywords
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