1,4 Butanediol (I,4 BD)

36th ECDD (2014) Agenda item 4.41,4‐Butanediol (I,4 BD)Gross behavior:1,4-BD has marked CNS effects. Administration of 500 mg/kg 1,4-BD (5.5 x 10-3mols/kg) to male Sprague-Dawley or Holtzman rats causes CNS depression and inducesa state resembling sleep or anesthesia characterized by loss of righting reflex, struggleresponse, and voluntary motor activity, but retention of the ability to respond to painand tactile stimuli 21. Very similar neuropharmacologic responses are observed afteradministration of GHB, except that sleep induction time (1.94x) and sleeping time(1.43x) are longer after administration of 1,4-BD than after administration of GHB 21.The LD50 via intraperitoneal injection for 1,4-BD is 1 g/kg, and more potent than theLD50 of 1.7 g/kg for GHB 21. Effects on EEG tracings are identical between 1,4-BDand GHB except for variations in time of onset, time of maximal effect, and duration ofthe anesthetic response 21. Administering 3 g/kg ethanol before, but not 30 min afteradministration of 1 g/kg 1,4-BD blocks the EEG effects induced by 1,4-BD 18.Administering ethanol with 1,4-BD also attenuates the rate-decreasing effects of 1,4-BDon operant responding maintained by food delivery in rats 22. The ability of ethanol toattenuate the effects of 1,4-BD on the EEG and on operant behavior suggests thatconversion of 1,4-BD to GHB is required considering that both drugs compete for thesame metabolic enzyme during their biotransformation (alcohol dehydrogenase)23.The induction of sleep by 1,4-BD in rats appears to track the emergence of GHB in thebrain 15. Roth and Giarman 15, reported that within 15 min of being administered 520mg/kg 1,4-BD i.v. significant increases in blood and brain concentrations of GHB occurin Sprague-Dawley rats, and these concentrations continued to increase to a maximumat approximately 60 min (blood) or 90 min (brain) after administration. These increasesin GHB blood and brain concentrations were accompanied by sleep onset 30 min afteradministration, and sleep continued until GHB levels returned to normal (approximately150 min after administration) 15.Consistent with a general depressant effect, 1,4-BD produces a dose-dependent loss ofthe righting reflex in rats, with a single 1 g/kg i.p. dose sustaining a loss of this reflexfor nearly 5.3 h 24. Significant disruption of rotorod performance is observed as low as200 mg/kg of 1,4-BD, and virtually complete suppression of locomotor activity isobserved at doses of 300 or 400 mg/kg 24.1,4-BD dose-dependently suppresses locomotor activity, produces catalepsy and ataxia,and causes a loss of the righting reflex in mice, but at differing relative potencies toGHB 25. The potency to produce catalepsy following intraperitoneal injection in mice issimilar between 1,4-BD (ED50 209.3 mg/kg) and GHB (ED50 221.0 mg/kg). 1,4-BDshows itself to be slightly more potent (ED50 177.6 mg/kg) than GHB (ED50 220.8mg/kg) in suppressing locomotor activity. However, 1,4-BD is over twice as potent asGHB to produce loss of the righting reflex (ED50 839.4 vs. 1702.7 mg/kg), and nearlythree times more potent to induce ataxia (ED50 197.7 vs. ED50 584.1 mg/kg) 25.Pharmacodynamic effects related to abuse of 1,4-BDPharmacological effects related to the abuse potential of 1,4-BD are discussed below inSections 7 and 8. In brief, 1,4-BD completely occasions the GHB discriminativestimulus in rats e.g., 26, 27 and pigeons 28, but does not fully generalize to benzodiazepineor pentobarbital discriminative stimuli in rats, pigeons or rhesus monkeys 29, 30, 31, 32 orto phencyclidine or heroin stimuli in rats 33. 1,4-BD appears inactive as an analgesic in avariety of mouse models and neither substitutes for morphine nor exacerbateswithdrawal in the morphine-dependent rhesus monkey 34.Page 11 of 33

36th ECDD (2014) Agenda item 4.41,4‐Butanediol (I,4 BD)Effects on respiration and cardiovascular functionLittle information is available regarding the direct actions of 1,4-BD on respiration orcardiovascular function. It’s metabolite, GHB, is a cardiovascular stimulant 35, 36, 37.GHB elicits marked and prolonged increases in mean arterial pressure and heart ratethat are reversed by the intravenous and intracerebroventricular administration of theGABA-B receptor antagonist, CGP 35348 38. In another study using radio telemetry inconscious rats, 1,4-BD increased mean arterial pressure and heart rate 22. Theseincreases were attenuated by the concurrent administration of ethanol indicating thatthese cardiovascular effects of 1,4-BD required the conversion of 1,4-BD to GHB 22.Effects in humans under controlled conditionsThai and colleagues compared the pharmacology of 1,4-BD and GHB after oraladministration of 25 mg/kg 1,4-BD in a single dose to healthy volunteers 12. Vital signswere monitored and subjective mood and symptoms were assessed using a visual analogscale (VAS). Serial blood samples were taken over a 24-hr period and analyzed byGC/MS for 1,4-BD and GHB levels. Results were summarized as follows: “1,4-BD wasquickly absorbed and cleared, with time to maximal plasma concentration of 24 12min, and elimination half-life (T1/2) of 39.3 11 min. 1,4-BD was extensively convertedto GHB, with a mean maximum GHB concentration of 45.6 19.7mg/l reached 39.4 11.2 min after 1,4-BD ingestion. GHB T1/2 averaged 32.3 6.6 min. Some subjectsexhibited slow oral clearance of 1,4-BD, which tended to correlate with a varianthaplotype of the alcohol dehydrogenase gene ADH-1B variant G143A. Mean clearance(CL/F) was 151.5 176.5 ml/min/kg for four subjects with variant haplotype versus598.8 446.6 ml/min/kg for four wild-type subjects (P 0.061). Subjects reportedfeeling less awake and alert, less able to concentrate, and more lightheaded in the first90 min after 1,4-BD ingestion. Pulse oximetry readings were lower 45 min after 1,4BD dosing with a mean oxygen saturation of 98.5% with 1,4-BD versus 99.6% withplacebo (P 0.031). Transient increases in mean systolic and diastolic blood pressurewere observed, but other vital signs remained unchanged. 1,4-BD was extensivelyconverted to GHB after oral administration, but significant inter-individual variability inthe rate of metabolism, possibly related to variants in ADH-1B, was observed. At themodest dose studied, significant clinical effects were not seen.4.2.Routes of administration and dosageThere are no therapeutic uses. Doses used in abuse are discussed in Section 13 below.4.3.Pharmacokinetics1,4-BD is quickly absorbed and cleared following oral administration to humansubjects. Time to maximal plasma concentration is 24 12 min with an elimination halflife (T1/2) of 39.3 11 min 12. The major biotransformation route of 1,4-BD is oxidationto GHB in rats 11, 20, 23, rhesus monkeys 39 and in humans 12, 39. Emergence of GHBfollowing administration of 1,4-BD is rapid and can occur within 5 min of oraladministration 12 and has a 2-min Tmax after a single intravenous dose of 1,4-BD 39,although there can be considerable variability across subjects in these values 12.Following a 25 mg/kg oral dose of 1,4-BD, the average Cmax for GHB was 45.6 mg/l,more than 10-fold higher than the Cmax for 1,4-BD, which averaged 3.8 mg/l 12. Theelimination half-life averaged 39.3 11.0 min for 1,4-BD and 32.3 6.6 min for GHB.Plasma levels of both substances were below the limit of quantitation of 1 mg/l by 4 hafter dosing 12.Page 12 of 33

36th ECDD (2014) Agenda item 4.41,4‐Butanediol (I,4 BD)1,4-BD is first oxidized to gamma-hydroxybutyraldehyde by alcohol dehydrogenase.The intermediate aldehyde is oxidized by aldehyde dehydrogenase to GHB. GHB issubsequently oxidized to succinic semialdehyde by cytosolic and mitochondrial GHBdehydrogenases 23. Because the enzymes responsible for converting 1,4-BD are alsoresponsible for metabolizing alcohol, alcohol can inhibit the biotransformation to GHB18. Inhibition can be mutual, and co-administration of alcohol and 1,4-BD may result inenhanced in vivo drug exposure to both 40.5.Toxicology1,4-BD was selected for evaluation by the U.S. National Toxicology Program (NTP)“because of high production volume, the potential for worker exposure, the lack ofadequate toxicological characterization and the lack of evaluation for carcinogenicpotential.” A summary report was issued in 1996 23. This report contains an extensivereview of literature on the pharmacology, metabolism, disposition, toxicity, andcarcinogenicity of 1,4-BD based upon the NTP's own studies and those of others up tothe date of the report. Much of the following material referring to the NTP report isdirectly quoted from the NTP report itself.The acute toxicity studies are summarized in Table 1. The results were unremarkableexcept for the relatively low lethal potency of the substance in that in no studyinvolving the oral or intraperitoneal administration of 1,4-BD was the LD50 lower thanabout 1 g/kg body weight in the rat, mouse or guinea pig23.Page 13 of 33

36th ECDD (2014) Agenda item 4.41,4‐Butanediol (I,4 BD)Table 1: Results of acute and short-term studies involving oral and intraperitonealadministration to 1,4-butanediolAcute Toxicity Values for 1,4-Butanediol (adapted with modification from Irwin 1996)Species/StrainNumberRoute LD50aReferenceRat/Albino25 Male25 FemaleOral1,550 mg/kg41Rat/Wistar30 Male30 FemaleOral1,830 mg/kg2,000 mg/kg42Rat/—b—Oral1,525 mg/kg43Rat/Wistar18 Male18 FemaleIntraperitoneal1,070 mg/kg44Rat/Albino88 Male 21Intraperitoneal1,000 mg/kgRat/Sprague-Dawley— 24Intraperitoneal1,328 mg/kgMouse/—— 45Oral2,180 mg/kgGuinea Pig90 43Oral2,000 mg/kgabLD50 median lethal doseData not providedRepeated-dose studies have been conducted in animals using gavage administration 42and inhalation exposure 45. Groups of eight male and eight female Wistar rats wereadministered 1,4-BD by gavage at doses of 5, 50, or 500 mg/kg for 28 days. There wereno deaths during the study. Mean body weights, organ weights, and feed consumptionof the different dose groups were similar to those of the controls. Mild-to-moderateinflammation of the liver was observed in some dosed animals, primarily from the 500mg/kg group, but the increased severity compared to that in the controls was notstatistically significant in males or females 42.Groups of 10 male Crl:CD rats were exposed nose only to an aerosol containing 0.2, 1,or 5 mg /L of 1,4-BD for 6 hours per day, 5 days per week for 2 weeks 45. No effectsassociated with chemical exposure were observed in rats exposed to 0.2 or 1 mg /L 1,4BD. Rats exposed to 5 mg/l exhibited lower (7% to 9%) mean body weights than airexposed controls. Rats receiving 10 exposures had slight atrophy of the lymphoid cellsof the thymus. After 14 days of recovery, mean body weights returned to control valuesand no indication of thymic atrophy was reported 45.In a study sponsored by the NTP, the developmental toxicity of 1,4-butanediol wasevaluated by administering 1, 100, 300, or 600 mg/kg by gavage in water to timedpregnant Swiss albino mice on gestation days 6 through 1546. No maternal deathsoccurred during the study; however, signs of acute CNS intoxication includinghypoactivity, immobility, and loss of righting reflex occurred after dosing in the 300and 600 mg/kg groups, but usually resolved within 4 hours after dosing. No apparenttolerance was noted during the 10-day dosing period. Other indications of maternaltoxicity included body and liver weights and feed consumption that were lower thanPage 14 of 33

36th ECDD (2014) Agenda item 4.41,4‐Butanediol (I,4 BD)those of the controls in the 300 and 600 mg/kg groups and kidney weight lower thanthat of controls in the 600 mg/kg group. Significant reductions in live fetal weightoccurred in the 300 and 600 mg/kg groups. The incidence of resorptions was notincreased by chemical exposure, and the percentage of litters with one or more late fetaldeaths was actually lower in the 300 and 600 mg/kg groups than in the control or 100mg/kg groups. The incidence of fetuses with external or visceral malformations wassimilar in all groups; however, there was an increasing trend in skeletal malformations(missing or branched ribs and fused thoracic vertebrae), primarily in the 600 mg/kggroup.In genotoxicity and carcinogenicity studies, 1,4-Butanediol was negative in Salmonellamutagenicity tests 47, 48 (as reported by Irwin, 2006 49). 1,4-BD also failed to produceclastogenicity or polyploidy in CHL/IU cells 48 (as reported by Irwin, 2006 49). 1,4Butanediol has not been evaluated for chronic toxicity or carcinogenicity 49. However,Irwin in his review of the relevant literature for the NTP, and in light of the rapidconversion of 1,4-BD to GHB concluded, "Because of the absence of evidence forgenotoxicity of 1,4-butanediol, coupled with the fact that the chronic toxicity andcarcinogenicity of γ-hydroxybutyric acid was in effect fully evaluated in NTPprechronic and chronic studies with γ-butyrolactone, demonstrating a lack of organspecific toxicity or carcinogenic potential, it is concluded that 1,4-butanediol would benegative in a similar chronic toxicity and carcinogenicity study. For these reasons it isthe opinion of the National Toxicology Program that 1,4-butanediol is not carcinogenicin animals (NTP, 1996), and no further cancer evaluation of this substance is needed."49.6.Adverse reactions in humansFor a number of reasons, one is unable to obtain precise data on the incidence ofadverse effects of 1,4-BD in humans. This is primarily due to the fact most of theadverse effects reported are due to the rapid conver

GBL) in urine has been developed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis 6. In addition, a sensitive measure for determining these levels in whole blood has also been developed using LC– MS/MS analysis with a limit of detection of 0.02 mg/L for 1,4-BD in ante mortem blood 7. Other methods are available for .File Size: 305KBPage Count: 33