The illicit recreational drug of abuse, γ-hydroxybutyrate (GHB) is a potent central nervous system depressant and is often encountered during forensic investigations of living and deceased persons. The sodium salt of GHB is registered as a therapeutic agent (Xyrem®), approved in some countries for the treatment of narcolepsy-associated cataplexy and (Alcover®) is an adjuvant medication for detoxification and withdrawal in alcoholics. Trace amounts of GHB are produced endogenously (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Available information indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, especially via binding to the GABA-B receptor subtype. Although GHB is listed as a controlled substance in many countries abuse still continues, owing to the availability of precursor drugs, γ-butyrolactone (GBL) and 1,4-butanediol (BD), which are not regulated. After ingestion both GBL and BD are rapidly converted into GHB (t½ ~1 min). The Cmax occurs after 20-40 min and GHB is then eliminated from plasma with a half-life of 30-50 min. Only about 1-5% of the dose of GHB is recoverable in urine and the window of detection is relatively short (3-10 h). This calls for expeditious sampling when evidence of drug use and/or abuse is required in forensic casework. The recreational dose of GHB is not easy to estimate and a concentration in plasma of ~100 mg/L produces euphoria and disinhibition, whereas 500 mg/L might cause death from cardiorespiratory depression. Effective antidotes to reverse the sedative and intoxicating effects of GHB do not exist. The poisoned patients require supportive care, vital signs should be monitored and the airways kept clear in case of emesis. After prolonged regular use of GHB tolerance and dependence develop and abrupt cessation of drug use leads to unpleasant withdrawal symptoms. There is no evidence-based protocol available to deal with GHB withdrawal, apart from administering benzodiazepines.

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Variability in the rate and extent of absorption, distribution and elimination of ethanol has important ramifications in clinical and legal medicine. The speed of absorption of ethanol from the gut depends on time of day, drinking pattern, dosage form, concentration of ethanol in the beverage, and particularly the fed or fasting state of the individual. During the absorption phase, a concentration gradient exists between the stomach, portal vein and the peripheral venous circulation. First-pass metabolism and bioavailability are difficult to assess because of dose-, time- and flow-dependent kinetics. Ethanol is transported by the bloodstream to all parts of the body. The rate of equilibration is governed by the ratio of blood flow to tissue mass. Arterial and venous concentrations differ as a function of time after drinking. Ethanol has low solubility in lipids and does not bind to plasma proteins, so volume of distribution is closely related to the amount of water in the body, contributing to sex- and age-related differences in disposition. The bulk of ethanol ingested (95-98%) is metabolised and the remainder is excreted in breath, urine and sweat. The rate-limiting step in oxidation is conversion of ethanol into acetaldehyde by cytosolic alcohol dehydrogenase (ADH), which has a low Michaelis-Menten constant (Km) of 0.05-0.1 g/L. Moreover, this enzyme displays polymorphism, which accounts for racial and ethnic variations in pharmacokinetics. When a moderate dose is ingested, zero-order elimination operates for a large part of the blood-concentration time course, since ADH quickly becomes saturated. Another ethanol-metabolising enzyme, cytochrome P450 2E1, has a higher Km (0.5-0.8 g/L) and is also inducible, so that the clearance of ethanol is increased in heavy drinkers. Study design influences variability in blood ethanol pharmacokinetics. Oral or intravenous administration, or fed or fasted state, might require different pharmacokinetic models. Recent work supports the need for multicompartment models to describe the disposition of ethanol instead of the traditional one-compartment model with zero-order elimination. Moreover, appropriate statistical analysis is needed to isolate between- and within-subject components of variation. Samples at low blood ethanol concentrations improve the estimation of parameters and reduce variability. Variability in ethanol pharmacokinetics stems from a combination of both genetic and environmental factors, and also from the nonlinear nature of ethanol disposition, experimental design, subject selection strategy and dose dependency. More work is needed to document variability in ethanol pharmacokinetics in real-world situations.

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Aims To investigate the absorption, distribution and elimination of ethanol in women with abnormal gut as a result of gastric bypass surgery. Patients who undergo gastric bypass for morbid obesity complain of increased sensitivity to the effects of alcohol after the operation. Methods Twelve healthy women operated for morbid obesity at least 3 years earlier were recruited. Twelve other women closely matched in terms of age and body mass index (BMI) served as the control group. After an overnight fast each subject drank 95% v/v ethanol (0.30 g kg -1 body weight) as a bolus dose. The ethanol was diluted with orange juice to 20% v/v and finished in 5 min. Specimens of venous blood were taken from an indwelling catheter before drinking started and every 10 min for up to 3.5 h post-dosing. The blood alcohol concentration (BAC) was determined by headspace gas chromatography. ResultsThe maximum blood-ethanol concentration ( C max ) was 0.741 ± 0.211 g l -1 ( ± s.d.) in the operated group compared with 0.577 ± 0.112 g l -1 in the controls (mean difference 0.164 g l -1 , 95% confidence interval (CI) 0.021, 0.307). The median time to peak ( t max ) was 10 min in the bypass patients compared with 30 min in controls (median difference -15 min (95% CI -10, -20 min). At 10 and 20 min post-dosing the BAC was higher in the bypass patients ( P < 0.05) but not at 30 min and all later times ( P > 0.05). Other pharmacokinetic parameters of ethanol were not significantly different between the two groups of women ( P > 0.05). Conclusions The higher sensitivity to ethanol after gastric bypass surgery probably reflects the more rapid absorption of ethanol leading to higher C max and earlier t max . The marked reduction in body weight after the operation might also be a factor to consider if the same absolute quantity of ethanol is consumed.

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The ratio of blood-alcohol concentration (BAC) to breath-alcohol concentration (BrAC) was determined for 799 individuals apprehended for driving under the influence of alcohol (DUI) in Sweden. The BrAC was determined with an infrared analyzer (Intoxilyzer 5000S) and venous BAC was measured by headspace gas chromatography. The blood samples were always taken after the breath tests were made and the average time delay was 30 ± 12 min (± SD), spanning from 6 to 60 min. The blood/breath ratios of alcohol decreased as the time between sampling blood and breath increased (F = 15.4, p &lt; 0.001), being 2337 ± 183 (6 to 15 min), 2302 ± 202 (16 to 30 min), 2226 ± 229 (31 to 45 min), and 2170 ± 225 (46 to 60 min). When the BAC was corrected for the metabolism of alcohol at a rate of 0.019 g%/h, the mean blood/breath ratios were 2395 ± 193 (6 to 15 min), 2416 ± 211 (16 to 30 min), 2406 ± 223 (31 to 45 min), and 2407 ± 210 (45 to 60 min); no significant differences (F = 0.197, p &gt; 0.05). The overall mean time-adjusted blood/breath ratio (± SD) was 2407 ± 213 and the 95% limits of agreement (LOA) were 1981 and 2833. During 1992, 1993, and 1994, the mean blood/breath ratios of alcohol were remarkably constant, being 2409 ± 288, 2407 ± 206, and 2421 ± 235, respectively, and the values were not significantly influenced by the person's age, gender, or blood-alcohol content. In 34 individuals (4.3%), the blood/breath ratio was less than 2100 after compensating for metabolism of alcohol between the times of sampling blood and breath. This compares with 156 individuals (19.6%) having a blood/breath ratio less than 2100:1 without making any correction for the metabolism of alcohol.