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Biomedical subjects

Neal L Benowitz

Publications and source records attributed to Neal L Benowitz.

At least 19 recordsLinked to original sources
PubMed2007

Determination of phenolic metabolites of polycyclic aromatic hydrocarbons in human urine as their pentafluorobenzyl ether derivatives using liquid chromatography-tandem mass spectrometry.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, and a number of them are carcinogenic. One approach for measuring exposure to them is to determine the concentrations of metabolites in urine. The pyrene metabolite 1-hydroxypyrene has been used as a biomarker for exposure in numerous studies. However, determination of exposure to several PAHs may be advantageous, since the relative amounts may vary depending upon the exposure source. We developed a liquid chromatography-tandem mass spectrometry method for the determination of phenolic metabolites of naphthalene, fluorene, phenanthrene, and pyrene in human urine. Following enzymatic cleavage of the glucuronide and sulfate conjugates, the phenolic metabolites are extracted from urine and converted to pentafluorobenzyl ethers. These derivatives greatly enhance the sensitivity of detection by atmospheric pressure chemical ionization in the negative ion mode. Lower limits of quantitation range from 0.01 to 0.5 ng/mL. Stable isotope-labeled internal standards were synthesized or obtained commercially. Data on urinary excretion of several PAH metabolites in urine of smokers and nonsmokers are presented.

Chromatography, Liquid↗
PubMed2007

Prediction methods for nicotine clearance using cotinine and 3-hydroxy-cotinine spot saliva samples II. Model application.

To develop and compare methods that predict individual nicotine (NIC) clearance, which reflects CYP2A6 activity, using random saliva cotinine (COT) and trans 3'-hydroxycotinine (3HC) measurements. COT and 3HC saliva concentrations in smokers were simulated utilizing a mechanistic population pharmacokinetic model of NIC metabolism that was adapted from the one described in a companion paper. Four methods to predict NIC clearance using the metabolites concentrations were compared. The precision bias, and the fraction of predictions that are made with an absolute error below 25% were the performance measures evaluated. Four prediction methods were compared: (M1) reference method, an intercept slope model of the metabolite concentration ratios ([3HC]/[COT]) (M2) an intercept slope model of the natural logarithm of the metabolite ratios (M3) a spline of the logarithm of the metabolite ratios (M4) Maximal Posteriori Bayesian estimate of NIC clearance conditioned on the model, COT and 3HC concentrations. In addition, the effect of smoking patterns on the concentrations of COT and 3HC was evaluated. The precision, accuracy, and the fraction of predictions with an absolute error below 25%, were higher for methods M2-M4 compared to method M1. However, the differences between M2 and M4 were small. Additionally, smoking pattern did not affect the metabolite concentration profiles. Predicting NIC clearance using an intercept slope model of the natural logarithm of the ratio of 3HC to COT appears to be a relatively simple method that is better than using the metabolite ratio directly. This method has a bias of approximately -10%, precision of approximately 60%. The fraction of estimates below an absolute error of 25% is 43%. These results support use of M2 to estimate CYP2A6 activity in smokers in the clinical setting.

Aryl Hydrocarbon Hydroxylases↗
PubMed2007

Population pharmacokinetics of nicotine and its metabolites I. Model development.

We present a mechanistic population model for the pharmacokinetics of nicotine (NIC), its primary (CYP2A6-generated) metabolite cotinine (COT), and COT's primary (CYP2A6-generated) metabolite, trans-3'-hydroxycotinine (3HC). Sixty-six subjects received oral deuterium-labeled NIC (NIC-d(2), 2 mg), and COT (COT-d(4), 10 mg) simultaneously. Frequent plasma/saliva samples were taken for measurement of concentrations of NIC-d(2), COT-d(2), 3HC-d(2), COT-d(4), and 3HC-d(4). A mechanistic population pharmacokinetic model was fitted to all data simultaneously. Most of the pharmacokinetic parameters found here agree with previous studies and with a previous model-independent analysis of these data. However, 3HC t(1/2) was found to be considerably shorter than a previously reported value, possibly because 3HC elimination was saturated with the larger doses used in the previous study. Additionally, the delay in the appearance of COT-d(2) in the blood was modeled as a time delay (t(1/2) = 12 min) in its release from the liver following NIC-d(2) administration. The most important result of the previous model-independent analysis of these data, confirmed here, is that NIC clearance to COT and the 3HC:COT saliva concentration ratio are highly correlated (r = 0.7-0.8). The correlation above support that idea that the 3HC:COT ratio can be used as a predictor of CYP2A6 activity and nicotine clearance. The model-based analysis extends and further justifies this conclusion.

Administration, Oral↗
PubMed2006

Pharmacogenomics: challenges and opportunities.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Clinical Medicine↗
PubMed2006

Cotinine concentration in smokers from different countries: relationship with amount smoked and cigarette type.

This four-country study examined salivary cotinine as a marker for nicotine intake and addiction among smokers in relation to numbers and types of cigarettes smoked. Smoking characteristics of cigarette smokers in Brazil, China, Mexico, and Poland were identified using a standard questionnaire. Cotinine concentration was measured using a saliva sample from each participant; its relationship with numbers and types of cigarettes smoked was quantified by applying regression techniques. The main outcome measure was salivary cotinine level measured by gas chromatography. In all four countries, cotinine concentration increased linearly with cigarettes smoked up to 20 per day [11.3 ng/mL (95% confidence interval, 10.5-12.2)] and then stabilized as the number of cigarettes exceeded 20 [6.8 ng/mL per cigarette (95% confidence interval, 6.3-7.4) for up to 40 cigarettes]. On average, smokers of regular cigarettes consumed more cigarettes and had higher cotinine levels than light cigarette smokers. Cotinine concentration per cigarette smoked did not differ between regular and light cigarette smokers. Results suggest a saturation point for daily nicotine intake and minimal or no reduction in nicotine intake by smoking light cigarettes.

Adolescent↗
PubMed2006

Guidelines on nicotine dose selection for in vivo research.

RATIONALE: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure. OBJECTIVES: This review capitalizes on the authors' collective decades of in vivo nicotine experimentation to clarify the issues and to identify the variables to be considered in choosing a dosaging regimen. Nicotine dose ranges tolerated by humans and their animal models provide guidelines for experiments intended to extrapolate to human tobacco exposure through cigarette smoking or nicotine replacement therapies. Just as important are the nicotine dosaging regimens used to provide a mechanistic framework for acquisition of drug-taking behavior, dependence, tolerance, or withdrawal in animal models. RESULTS: Seven species are addressed: humans, nonhuman primates, rats, mice, Drosophila, Caenorhabditis elegans, and zebrafish. After an overview on nicotine metabolism, each section focuses on an individual species, addressing issues related to genetic background, age, acute vs chronic exposure, route of administration, and behavioral responses. CONCLUSIONS: The selected examples of successful dosaging ranges are provided, while emphasizing the necessity of empirically determined dose-response relationships based on the precise parameters and conditions inherent to a specific hypothesis. This review provides a new, experimentally based compilation of species-specific dose selection for studies on the in vivo effects of nicotine.

Animals↗
PubMed2006

Mutagen sensitivity has high heritability: evidence from a twin study.

Despite numerous studies showing that mutagen sensitivity is a cancer predisposition factor, the heritability of mutagen sensitivity has not been clearly established. In this report, we used a classic twin study design to examine the role of genetic and environmental factors on the mutagen sensitivity phenotype. Mutagen sensitivity was measured in peripheral blood lymphocytes from 460 individuals [148 pairs of monozygotic (MZ) twins, 57 pairs of dizygotic (DZ) twins, and 50 siblings]. The intraclass correlation coefficients were all significantly higher in MZ twins than in dizygotes (DZ pairs and MZ-sibling pairs combined) for sensitivity to four different mutagen challenges. Applying biometric genetic modeling, we calculated a genetic heritability of 40.7%, 48.0%, 62.5%, and 58.8% for bleomycin, benzo[a]pyrene diol epoxide, gamma-radiation, and 4-nitroquinoline-1-oxide sensitivity, respectively. This study provides the strongest and most direct evidence that mutagen sensitivity is highly heritable, thereby validating the use of mutagen sensitivity as a cancer susceptibility factor.

Genetic Predisposition to Disease↗
PubMed2006

Characterization of the novel CYP2A6*21 allele using in vivo nicotine kinetics.

OBJECTIVE: The impact of CYP2A6*21 (K476R) on in vivo nicotine metabolism and disposition was investigated. METHODS: A two-step allele-specific PCR assay was developed to detect the 6573A>G single nucleotide polymorphism (SNP) in CYP2A6*21. Nicotine metabolism phenotypes from a previously described intravenous labeled nicotine and cotinine infusion study [1] was used to assess the impact of CYP2A6*21. Genomic DNA samples from 222 (111 monozygotic and dizygotic twin pairs) Caucasian subjects were genotyped for CYP2A6 alleles (CYP2A6*1X2, -*1B, -*2, -*4, -*7, -*9, -*10, -*12, and -*21). The pharmacokinetic parameters were compared between individuals with no detected CYP2A6 variants (CYP2A6*1/*1, n = 163) and individuals heterozygous for the CYP2A6*21 allele (CYP2A6*1/*21, n = 9). RESULTS: The frequency of the CYP2A6*21 allele was found to be 2.3% in Caucasians (n = 5/222 alleles, evaluated in one twin from each twin pair). In vivo pharmacokinetic parameters, such as nicotine clearance (1.32+/-0.37 vs. 1.18+/-0.20 L/min), fractional clearance of nicotine to cotinine (1.02+/-0.36 vs. 0.99+/-0.23 L/min), nicotine half-life (111+/-37 vs. 116+/-29 min), and the trans-3'-hydroxycotinine to cotinine ratio (1.92+/-1.0 vs. 1.55+/-0.58) indicated no substantial differences in nicotine metabolism between those without the variant (CYP2A6*1/*1, n = 163) and those with the variant (CYP2A6*1/*21, n = 9), respectively. CONCLUSIONS: CYP2A6*21 does not have a detectable impact on nicotine metabolism in vivo. Our data suggest that CYP2A6*21 may not be important for future studies of nicotine metabolism and the resulting impacts on smoking behaviors.

Alleles↗
PubMed2006

Caffeine metabolites in umbilical cord blood, cytochrome P-450 1A2 activity, and intrauterine growth restriction.

Studies investigating antenatal caffeine consumption and reproductive outcomes show conflicting results, and most studies have used maternal self-reported caffeine consumption to estimate fetal exposure. This study (n=1,606) was specifically designed to test the association of caffeine and its primary metabolites in umbilical cord blood with intrauterine growth restriction (IUGR). Pregnant women were recruited from 56 obstetric practices and 15 clinics affiliated with six hospitals in Connecticut and Massachusetts between September 1996 and January 2000. In an adjusted model including caffeine only, levels in all quartiles were associated with reduced risk of IUGR. In adjusted analyses including paraxanthine and caffeine, serum paraxanthine levels in the highest quartile were associated with increased risk of IUGR (adjusted odds ratio=3.29, 95% confidence interval: 1.17, 9.22); caffeine remained protective. These conflicting findings suggest that cytochrome P-450 1A2 (CYP1A2) metabolic activity may be associated with IUGR, so the ratio of paraxanthine to caffeine was then modeled. The likelihood of IUGR increased 21% for every one standard deviation change in the ratio (adjusted odds ratio=1.21, 95% confidence interval: 1.07, 1.37), suggesting that CYP1A2 activity, and not the absolute levels of paraxanthine, influences fetal growth. No associations were observed between caffeine or any metabolites and preterm delivery.

Adult↗
PubMed2006

Female sex and oral contraceptive use accelerate nicotine metabolism.

BACKGROUND: Several studies have reported that female smokers have a higher risk of lung cancer than male smokers. This could be related to sex differences in nicotine metabolism and related smoking behavior. This study tested the hypothesis that women metabolize nicotine more rapidly than men and that, among women, oral contraceptive users metabolize nicotine more rapidly than nonusers of oral contraceptives. METHODS: Two hundred seventy-eight healthy volunteers who were twins and 16 who were siblings of twins, recruited from the Northern California Twin Registry, received an infusion of deuterium-labeled nicotine and cotinine with frequent blood sampling. The plasma clearances of nicotine and cotinine, the clearance of nicotine to cotinine (an index of cytochrome P450 [CYP] 2A6 activity), and the ratio of trans-3'-hydroxycotinine to cotinine (another indicator of CYP2A6 activity) were measured. RESULTS: The clearances of nicotine and cotinine, the clearance of nicotine to cotinine, and the trans-3'-hydroxycotinine/cotinine ratio were significantly higher in women than in men (nicotine clearance, 15.6 +/- 4.3 mL.min(-1).kg(-1) in men versus 18.8 +/- 6.6 mL.min(-1).kg(-1) in women; P < .001); they were also higher among women taking oral contraceptives than in those who were not taking oral contraceptives (nicotine clearance, 22.5 +/- 6.6 mL.min(-1).kg(-1) in women taking oral contraceptives versus 17.6 +/- 6.1 mL.min(-1).kg(-1) in those who were not; P < .05). Women who were menopausal or postmenopausal were not different from men. Among oral contraceptive users, nicotine metabolism was accelerated among those taking combined and estrogen-only contraceptives but not progesterone-only contraceptives. CONCLUSIONS: Sex hormones influence nicotine metabolism. Nicotine and cotinine metabolism is faster in women than in men and is faster in women taking oral contraceptives compared with those who are not. Accelerated nicotine metabolism appears to be a result of estrogen. Sex-related differences in nicotine clearance could affect smoking behaviors, as well as response to nicotine medications, and could be a marker for altered metabolism of nicotine-derived carcinogens.

Adolescent↗
PubMed2006

Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance.

BACKGROUND AND OBJECTIVE: Grapefruit juice is an inhibitor of the cytochrome P450 (CYP) 3A4 enzyme and transporters such as P-glycoprotein and organic anion transporting polypeptides, leading to clinically important interactions. Our objective was to study the effect of grapefruit juice on the pharmacokinetics of nicotine, which is primarily metabolized by the CYP2A6 enzyme. METHODS: Ten volunteers were given a 2-mg oral dose of deuterium-labeled nicotine on 3 occasions together with 1 L of water, full-strength grapefruit juice, or half-strength grapefruit juice. Concentrations of nicotine and its metabolites were analyzed in plasma and urine for 8 hours. RESULTS: Grapefruit juice inhibited the formation of cotinine from nicotine (area under the plasma cotinine concentration-time curve from 0 to 8 hours of 6807 min.ng/mL, 7805 min.ng/mL, and 8007 min.ng/mL for full-strength grapefruit juice, half-strength grapefruit juice, and water, respectively; repeated-measures ANOVA, P=.009). The time to peak plasma concentration of cotinine was delayed (216 minutes, 159 minutes, and 147 minutes, respectively; ANOVA, P=.011), and the peak plasma concentration was lower with grapefruit juice compared with water (18 ng/mL, 21 ng/mL, and 22 ng/mL, respectively; ANOVA, P=.010). Oral clearance, peak plasma concentration, and time to peak plasma concentration of nicotine were not affected. Grapefruit juice increased the renal clearance of nicotine (231 mL/min, 219 mL/min, and 123 mL/min, respectively; ANOVA, P=.045) and cotinine (19 mL/min, 14 mL/min, and 16 mL/min, respectively; ANOVA, P=.002). CONCLUSIONS: Grapefruit juice inhibits the metabolism of nicotine to cotinine, a pathway mediated by CYP2A6, and increases the renal clearance of nicotine and cotinine. Nicotine oral clearance is not affected by grapefruit juice because the inhibition of hepatic metabolism is offset by the increase in the renal clearance of nicotine. However, other compounds metabolized by CYP2A6, as well as other drugs excreted via renal clearance mechanisms similar to those of nicotine, may be susceptible to significant pharmacokinetic grapefruit juice interactions.

Administration, Oral↗
PubMed2006

CYP2A6 genotype and the metabolism and disposition kinetics of nicotine.

BACKGROUND AND OBJECTIVE: The liver enzyme cytochrome P450 (CYP) 2A6 is primarily responsible for the metabolism of nicotine. Variants in the CYP2A6 gene have been associated with altered nicotine metabolism and with effects on smoking behavior. Our objective was to determine the relationship between variant CYP2A6 genotypes and the disposition and metabolism of nicotine administered intravenously. METHODS: Intravenous infusions of deuterium-labeled nicotine and cotinine were administered to 278 healthy twin volunteers, most of whom were white. They were genotyped for CYP2A6*1, CYP2A6*2, CYP2A6*4, CYP2A6*7, CYP2A6*8, CYP2A6*9, CYP2A6*10, and CYP2A6*12. RESULTS: On the basis of the fractional clearance of nicotine to cotinine and on the plasma ratio of 3'-hydroxycotinine to cotinine, both shown to be indicators of CYP2A6 enzymatic activity, subjects were classified into 3 groups. Group 1 included wild-type variant CYP2A6*1/*1 (n=215) and was assumed to have 100% activity. Group 2 included *1/*9 (n=21) and *1/*12 (n=12), which averaged about 80% of normal activity. Group 3 included *1/*2 (n=10), *1/*4 (n=2), *9/*12 (n=3), *9/*4 (n=2), and *9/*9 (n=3), which averaged about 50% of normal activity. The mean total plasma clearance of nicotine (+/-SD) was 18.8+/-6.0, 15.5+/-4.9, and 11.7+/-5.1 mL.min-1.kg-1 in groups 1, 2, and 3, respectively, and group 1 had significantly faster clearance than group 2 (P<.05) and group 3 (P<.01). Overall, groups 2 and 3 also had lower total clearance of cotinine, had longer half-lives for nicotine and cotinine, and excreted in the urine a greater fraction of the nicotine dose as unchanged nicotine and nicotine glucuronide and excreted less as 3'-hydroxycotinine compared with group 1. CONCLUSIONS: We provide novel pharmacokinetic and metabolic data on nicotine after systemic dosing in relation to common CYP2A6 genotypes. Our data will enhance the interpretation of CYP2A6 genotypic data as used in association studies of smoking behavior and its health consequences.

Adolescent↗
PubMed2006

Nicotine intake and dose response when smoking reduced-nicotine content cigarettes.

OBJECTIVES: The progressive reduction of the nicotine content of cigarettes has been suggested as a way to wean smokers from nicotine and tobacco. As a first step in evaluating this strategy, we studied smokers smoking cigarettes containing tobacco with differing nicotine content. METHODS: Twelve healthy smokers participated in a semiblinded, within-subject, crossover study. Subjects were asked to smoke 1 of their usual brand of cigarette and then on 5 subsequent occasions to smoke a research cigarette, each with differing nicotine content. The research cigarettes contained 0.6 to 10.1 mg nicotine per cigarette. Plasma nicotine and blood carboxyhemoglobin levels, as well as subjective and cardiovascular responses, were measured after smoking. Systemic nicotine intake per cigarette was estimated by use of plasma nicotine concentrations over time and clearance data from the general population. RESULTS: Systemic nicotine intake (0.26-1.47 mg per cigarette) varied with nicotine content of the cigarette (r = 0.82, P < .001). Compensation when smoking single low-nicotine content cigarettes ranged from -1% (95% confidence interval, -23% to 21%) to 34% (95% confidence interval, -39% to 107%) for 1-mg to 8-mg research cigarettes. Carbon monoxide intake and estimated tar exposure were similar across cigarettes. Low-nicotine content cigarettes were rated as being of lower quality and less satisfying than the 12-mg research cigarette or the usual brand (P < .05 for both comparisons). Cigarette smoking increased heart rate and decreased skin temperature, but the nicotine dose-response curve flattened at higher doses, with a maximal response being observed in cigarettes at a nicotine content level of about 8 mg. CONCLUSIONS: Our study suggests that reduced-nicotine content cigarettes are reasonable candidates for trying to reduce the level of nicotine addiction in smokers. The flat nicotine dose-cardiovascular response curve is consistent with other studies demonstrating tolerance to the cardiovascular effects of nicotine.

Adult↗
PubMed2006

Biomarkers to assess the utility of potential reduced exposure tobacco products.

To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.

Biomarkers↗
PubMed2006

Biomarkers to assess the utility of potential reduced exposure tobacco products.

To date, we have no valid biomarkers that serve as proxies for tobacco-related disease to test potential reduced exposure products. This paper represents the deliberations of four workgroups that focused on four tobacco-related heath outcomes: Cancer, nonmalignant pulmonary disease, cardiovascular disease, and fetal toxicity. The goal of these workgroups was to identify biomarkers that offer some promise as measures of exposure or toxicity and ultimately may serve as indicators for future disease risk. Recommendations were based on the relationship of the biomarker to what is known about mechanisms of tobacco-related pathogenesis, the extent to which the biomarker differs among smokers and nonsmokers, and the sensitivity of the biomarker to changes in smoking status. Other promising biomarkers were discussed. No existing biomarkers have been demonstrated to be predictive of tobacco-related disease, which highlights the importance and urgency of conducting research in this area.

Biomarkers↗
PubMed2006

Intraindividual variability of plasma antioxidants, markers of oxidative stress, C-reactive protein, cotinine, and other biomarkers.

BACKGROUND: Within-person variability in biomarkers results in random error that can attenuate estimates of association. Little information on such variability is available for a number of nutrition-related biomarkers. METHODS: Blood samples obtained 2 to 4 weeks apart were analyzed for tocopherols, carotenoids, ascorbate, lipids, cotinine, C-reactive protein, and oxidative stress. Subjects (n = 206 men and women, mean age 45.4 years) were either smokers or passively exposed to smoke. We calculated intraindividual and interindividual variability and the number of measurements required to reduce attenuation. RESULTS: For most biomarkers, 2 measurements would be required to limit the attenuation of correlation coefficients to no lower than 90% of the true correlation. If only one measurement were obtained, observed correlations would be approximately 80-88% of true correlations. For regression coefficients, 3 or 4 measures would be required. Exceptions were ascorbic acid and malondialdehyde, for which a single measure resulted in little attenuation. CONCLUSIONS: For most serum markers, collection of 2 or more measurements per person is desirable to increase the ability to detect associations between biomarkers and health-related variables. If only one measure is possible, sample sizes should be planned to permit detection of associations that are likely to be observed, not the theoretical true associations. The results of this study, in which measurements were obtained 2 to 4 weeks apart, are relevant for epidemiologic research in which the exposure of interest is the subject's baseline or current status. It is likely that within-person variability would be greater over a period of months or years.

Adolescent↗
PubMed2006

Gamma-hydroxybutyrate and ethanol effects and interactions in humans.

BACKGROUND: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers. METHODS: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.6 g/kg ethanol in 2 doses, alone and combined in a double-blind, placebo-controlled, crossover study. Plasma concentrations, heart rate (HR), blood pressure (BP), and oxygen saturation (O2sat) were serially monitored for 24 hours. RESULTS: Adverse events included 2 instances of hypotension and 6 episodes of vomiting with GHB-plus-ethanol ingestion. Oxygen saturation was decreased by GHB and ethanol individually, and maximally decreased by the drugs combined (max -2.1% +/- 0.3%, P < 0.0001 vs placebo). Compared with baseline, systolic and diastolic BP were significantly decreased, and HR was increased by ethanol but not affected by GHB alone (maximum systolic BP change -15.7 +/- 3.0 mm Hg, P = 0.0006; maximum HR change 13.5 +/- 2.3 beats per minute, P = 0.006). Ethanol coingestion resulted in 16% higher GHB maximal plasma concentration and 29% longer elimination half-life, indicating possible enhanced bioavailability or reduced clearance of GHB caused by ethanol, however, these effects were not statistically significant. CONCLUSIONS: Modest doses of GHB do not affect hemodynamic function, but O2sat was decreased. Gamma-hydroxybutyrate-plus-ethanol resulted in more adverse effects, including gastrointestinal disturbances, hypotension, and decreased O2sat, but only minimal pharmacokinetic interactions were observed.

Adult↗