Pharmacokinetics of 1,4-butanediol in rats: bioactivation to gamma-hydroxybutyric acid, interaction with ethanol, and oral bioavailability

Ho-Leung Fung, Pei-Suen Tsou, Jurgen Bulitta, Doanh Tran, Nathaniel Page, David Soda, Sun Fung

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1,4-Butanediol (BD), a substance of abuse, is bioactivated to I?-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 (Michaelisa??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 (72.0A?9.1 min vs. 6.7A?0.6 min, respectively, p
Original languageEnglish
Pages (from-to)56 - 69
Number of pages14
JournalAAPS PharmSciTech
Issue number1
Publication statusPublished - 2008

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