Clinical pharmacology of 1,4-butanediol and gamma-hydroxybutyrate after 1,4-butanediol administration to healthy volunteers

1,4-Butanediol (BD) is converted to gamma-hydroxybutyrate (GHB) after ingestion, and is associated with cases of dependence, coma, and death. The pharmacology of BD after oral ingestion has not been described in humans. Eight healthy volunteers (five men) were administered 25 mg/kg BD in a single oral dose after an overnight fast in a double-blinded, placebo-controlled, crossover study. Vital signs were monitored, and serial blood samples collected over 24 h for gas chromatography-mass spectrometry analysis of BD and GHB levels. Subjective mood and symptoms responses were assessed by visual analog scale. All subjects completed the study without significant adverse effects. BD was quickly absorbed and cleared, with time-to maximal plasma concentration of 24 +/- 12 min, and elimination half-life (T-1/2) of 39.3 +/- 11 min. BD was extensively converted to GHB, with a mean maximum GHB concentration of 45.6 +/- 19.7 mg/l reached 39.4 +/- 11.2 min after BD ingestion. GHB T-1/2 averaged 32.3 +/- 6.6 min. Some subjects exhibited slow oral clearance of BD, which tended to correlate with a variant haplotype of the alcohol dehydrogenase gene ADH-IB G143A. Mean CL/F was 151.5 +/- 176.5 ml/min kg for four subjects with variant haplotype versus 598.8 +/- 446.6 ml/min kg for four wild-type subjects (P = 0.061). Subjects reported feeling less awake and alert, less able to concentrate, and more lightheaded in the first 90 min after BD ingestion. Pulse oximetry readings were lower 45 min after BD dosing with a mean oxygen saturation of 98.5% with 1313 versus 99.6% with placebo (P = 0.031). Transient increases in mean systolic and diastolic blood pressure were observed, but other vital signs remained unchanged. BD was extensively converted to GHB after oral administration, but significant inter-individual variability in the rate of metabolism, possibly related to variants in ADH-IB, was observed. At the modest dose studied, significant clinical effects were not seen.