Individual differences in the kinetics of alcohol absorption and elimination

The individual differences in alcohol pharmacokinetics were studied using the one-compartment model with first-order absorption and zero-order elimination kinetics in humans. The blood alcohol concentrations (BACs) were simulated by obtained parameters, absorption rate constant (ka), and climination rate constant (β). The 81 healthy young Japanese volunteers, who had been divided into those without alcohol-induced facial flushing (nonflushers) and those with facial flushing (flushers) according to alcohol patch test results and a questionnaire beforehand, ingested 0.50 g/kg ethanol within 1 minute. Breath alcohol concentrations (BrACs) were measured during absorption and during the elimination period. BACs were obtained based on BrACs. Fifteen percent of subjects exhibited low BAC profile (below 0.4 mg/mL) (first-pass effect [FPE] group), although the majority showed normal BAC profile (normal group). The ka was approximately 5 to 8 (h⁻¹) in the normal group without significant difference between nonflushers and flushers, whereas that in the FPE group was significantly smaller than in the normal group. For the normal group, peak BACs were well simulated by the one-compartment model with first-order absorption and zero-order elimination kinetics. A considerable portion of subjects exhibited FPE. Absorption of alcohol from the intestine plays an important role in alcohol pharmacokinetics in humans.     

Alcohol study on blood concentration estimation: Reliability and applicability of Widmark formula on Chinese male population

Widmark formula suggests estimating blood alcohol concentration level (BAC) on a given amount of alcohol administrated with knowledge of subject’s body weight and sex. The idea has been referenced extensively in forensic science with application in drink driving prosecution. A sample of Chinese subjects was collected in the drinking experiment, and in this study we mainly focus on the verification of the validity of Widmark formula on Chinese male population. A promising result is obtained where the extrapolated BAC measurement is directly proportional to the amount of alcohol administrated, and inversely to the subject’s body weight. The results noted in the general linear model is further supported by the nonlinear regression analysis and a concordant argument reaches by deploying the concept to the BAC level attained at peak.     

Ultra-rapid rate of ethanol elimination from blood in drunken drivers with extremely high blood-alcohol concentrations

The rate of alcohol elimination from blood was determined in drunken drivers by taking two blood samples about 1 h apart. These cases were selected because the individuals concerned had reached an extremely high blood-alcohol concentration (BAC) when they were apprehended. This suggests a period of continuous heavy drinking leading to the development of metabolic tolerance. Use of double blood samples to calculate the elimination rate of alcohol from blood is valid provided that drunken drivers are in the post-absorptive phase of the BAC curve, the time between sampling is not too short, and that zero-order elimination kinetics operates. Evidence in support of this came from other drunken drivers in which three consecutive blood samples were obtained at hourly intervals. The mean BAC (N = 21) was 4.05 g/l (range, 2.71–5.18 g/l), and the average rate of alcohol elimination from blood was 0.33 g l⁻¹ h⁻¹ with a range of 0.20–0.62 g l⁻¹ h⁻¹. The possibility of ultra-rapid rates of ethanol elimination from blood in drunken drivers having extremely high BAC deserves to be considered in forensic casework, e.g., when retrograde extrapolations and other blood-alcohol calculations are made. The mechanism accounting for more rapid metabolism is probably related to induction of the microsomal enzyme (CYP2E1) pathway for ethanol oxidation, as one consequence of continuous heavy drinking. However, the dose of alcohol and the duration of drinking necessary to boost the activity of CYP2E1 enzymes in humans have not been established.     

The estimation of blood alcohol concentration

Expert witnesses and others involved in toxicology are frequently asked to perform retrograde extrapolation of blood alcohol concentration (BAC) or to estimate BAC based on a proposed drinking scenario. Although many individuals are reluctant to perform these calculations and some jurisdictions expressly prohibit them, a significant number of practitioners routinely estimate BAC based on this type of calculation, using as a basis the fundamental work of Widmark. Although improvements to the Widmark formula and other data pertaining to the pharmacology of alcohol have been published, these improvements are frequently ignored when estimating BAC. This article summarizes five published models for the estimation of BAC and proposes a sixth model that incorporates recent data on the rate of absorption of alcohol from the GI tract into the existing five models. The five improved models can be computerized and used to construct comparative snapshots of the BACs calculated by the different algorithms. This will allow practitioners to provide a more balanced picture of the variability in BAC calculations.     

Computer simulation analysis of blood alcohol

A mathematical model using an iterative algorithm based on the Widmark formula is used to simulate a continuous spectrum of the expected blood alcohol concentration from start of alcohol dosage to time of specific event in numerical and graphic form. Absorption is based on flexible first order rates with provision for an optional good-fit model of the delaying effect of food. Elimination is based initially on selectable zero order rates followed by first order kinetics at low blood alcohol concentrations. A correlation coefficient of 0.94 was obtained in comparisons of projected to observed blood alcohol concentrations. A measurement of the area under the curve is provided. The software program utilizing the algorithm is suitable for forensic and clinical applications.     

Intra-individual and inter-individual variation in breath alcohol pharmacokinetics: Variation over three visits

Eleven male and 7 female student subjects underwent serial Breath Alcohol Concentration (BrAC) measurements after being given alcohol as 13% white wine (5.7 ml/kg for males and 4.7 ml/kg for females) in a fasting state on three separate occasions. BrAC versus time curves were constructed for each subject and the values of peak BrAC (C_max), theoretical BrAC extrapolated at zero time (Co), time taken to reach peak (T_max) and rate of elimination (ß) from breath were recorded directly from the curves. Average Intra-individual variation for each individual between the 3 visits (for males and females, respectively) was 5.6% and 8% for Co, 12% and 13% for C_max, 42% and 37% for T_max and 11% and 13% for ß. Inter-individual variation (for males and females) was 7.5% and 13% for Co, 16% and 15% for C_max, 43% and 46% for T_max and 21% and 15% for ß. Average elimination rates in males (5.3 μg/100 ml breath/h, range 4–7.7) and females (5.6 μg/100 ml breath/h, range 4–7) were not significantly different. Widmark factors calculated by various established mathematical methods were 0.71–0.81 in males and 0.59–0.68 in females, higher than the originally quoted mean experimental levels.     

Evaluating alleged drinking after driving--the hip-flask defence. Part 1. Double blood samples and urine-to-blood alcohol relationship

This two-part article examines the strengths and weaknesses of various ways of investigating claims of drinking alcohol after driving, commonly known as the hip-flask or glove-compartment defence. In many countries the onus of proof in hip-flask cases rests on the prosecution. With good co-operation from the police and timely sampling of body fluids, such as blood and urine for forensic analysis of ethanol, useful evidence can be mustered to support or challenge the truthfulness of alleged drinking after driving. The person's blood-alcohol concentration (BAC) can be compared with values expected on the basis of the amount of alcohol consumed after driving, according to theoretical Widmark calculations. The actual BAC measured is then adjusted for the additional amount of alcohol consumed in the after-drink. Double blood samples, that is, taking two specimens of venous blood about 30-60 minutes apart and looking at the magnitude and direction of change in BAC provides little or no more information than a single blood specimen. However, the relationship between alcohol in blood and urine is very useful in hip-flask cases whereby the concentration expected in the primary urine is compared with the concentration in the bladder urine voided. The concentration of alcohol determined in a second urine sample collected 30-60 min later gives supporting evidence in hip-flask cases. A graphical method, which entails plotting ethanol concentrations in blood and urine as a function of time provides a robust and practical way to investigate hip-flask defences. In the second part of the review, congener analysis is presented, which entails comparing the concentrations of n-propanol, isobutanol and occasionally other congeners in the alcoholic beverage allegedly consumed after driving with the volatiles present in the suspect's blood and urine determined by headspace gas chromatography.     

Hepatic metastases: in vivo assessment of perfusion parameters at dynamic contrast-enhanced MR imaging with dual-input two-compartment tracer kinetics model

This study was institutional review board approved, with waived patient consent for retrospective analysis of the data. The hepatic perfusion at dynamic contrast material-enhanced magnetic resonance (MR) imaging was commonly described and assessed by using a dual-input one-compartment tracer kinetics model. Although the tracer kinetics in normal liver parenchyma can be described by using a single compartment, functional changes in the tumor microenvironment can result in distinctly different tracer behavior that entails a second tissue compartment. A dual-input two-compartment model is proposed to describe the tracer behavior in hepatic metastases. The authors applied this model to the dynamic MR imaging data obtained in three patients. Perfusion parameter maps and region-of-interest analysis revealed that tracer behavior in hepatic metastases-in contrast to that in surrounding normal liver tissue, which effectively involves one compartment-can be described by using two compartments.     

"Cognac alibi" as a drunk-driving defense and medico-legal challenge

Some drivers with positive forensic ethanol analyses, offer an explanation that they consumed alcohol a short time before a traffic accident or after driving. In medico legal practice this is commonly known as hip-flask defense, but to us as "cognac alibi" defense. In these cases, the lawyers require the medico legal experts to offer as much information as possible so that the court may come to the most reliable conclusions about the driver's blood alcohol concentration at the moment of the traffic accident (BAC(Acc)). At the Institute of Forensic Medicine our own analytical approach was established to study this medico legal problem. It consists of three inter-related phases in which it combines the obtained BAC values, with testimonies of the drunk driving suspect andalso witnesses. A specific algorithm was designed for calculating absorption and elimination of consumed alcohol. All the above-mentioned elements and blood-ethanol values calculated according to Widmark's method were inserted into appropriate cells of MS Excel software in order to calculate BAC in the function of time. The result is a relevant analysis of the drunk driving suspect's BAC in 5-minute intervals, as well as a graphic representation in chart form.     

Quantification of myocardial blood flow with <Superscript>82</Superscript>Rb dynamic PET imaging

Purpose The PET tracer ⁸²Rb is commonly used to evaluate regional perfusion defects for the diagnosis of coronary artery disease. There is limited information on the quantification of myocardial blood flow and flow reserve with this tracer. The goal of this study was to investigate the use of a one-compartment model of ⁸²Rb kinetics for the quantification of myocardial blood flow. Methods Fourteen healthy volunteers underwent rest and dipyridamole stress imaging with both ¹³N-ammonia and ⁸²Rb within a 2-week interval. Myocardial blood flow was estimated from the time-activity curves measured with ¹³N-ammonia using a standard two-compartment model. The uptake parameter of the one-compartment model was estimated from the time-activity curves measured with ⁸²Rb. To describe the relationship between myocardial blood flow and the uptake parameter, a nonlinear extraction function was fitted to the data. This function was then used to convert estimates of the uptake parameter to flow estimates. The extraction function was validated with an independent data set obtained from 13 subjects with documented evidence of coronary artery disease (CAD). Results The one-compartment model described ⁸²Rb kinetics very well (median R-square = 0.98). The flow estimates obtained with ⁸²Rb were well correlated with those obtained with ¹³N-ammonia (r = 0.85), and the best-fit line did not differ significantly from the identity line. Data obtained from the subjects with CAD confirmed the validity of the estimated extraction function. Conclusion It is possible to obtain accurate estimates of myocardial blood flow and flow reserve with a one-compartment model of ⁸²Rb kinetics and a nonlinear extraction function.     

Alleged drug facilitated sexual assault (DFSA) in Northern Ireland from 1999 to 2005. A study of blood alcohol levels

Alleged sexual assault cases, identified from the forensic science Northern Ireland (FSNI) database, which had toxicology assays carried out on either blood or urine samples, were examined for the years 1999 up to and including 2005. In 1999 there were 30 toxicology requests while in 2005 there were 51, representing a 70% increase. The percentage of cases containing alcohol, drugs or both increased from 66% in 1999 to 78% in 2005. The estimated average blood alcohol concentration remained broadly similar throughout the spread of years. It was found to be 218mg% (milligrams per 100 millilitres) in 1999 and 217mg% in 2005. The actual number of cases studied within the 12h cut-off time rose from 9 in 1999 to 22 in 2005. The relationship between negative toxicology results and time delay between the alleged assault and forensic sampling was examined. This showed that between 44% and 74% of cases were found to have a time delay of >12h. Some of these cases may therefore represent false negative results. The presence of drugs, either alone or in combination with other drugs, doubled between 1999 and 2005. Increased identification was found with antidepressants, recreational drugs, benzodiazepines and analgesics, some of which were also associated with alcohol consumption. The findings are sufficient to cause alarm for the health and safety of certain individuals and their increased vulnerability to sexual assault in some social settings. Additionally, the legal implications of what constitutes valid consent needs to be considered further in the light of these findings, if attrition rates are to improve.     

Ophthalmologic examinations under the acute influence of alcohol

Alcohol is the most widely used recreational drug in Western countries. It affects the psychophysical performance in different ways, e.g. by reducing cognitive functions, causing coordination disturbances or impairing vision. Visual impairments both concern oculomotor and visual sensory functions, such as decreased mesopic vision, decreased field of vision and an increase of saccadic eye movements.During cycling trials with alcoholised test persons, repeated measurements of (1.) the time needed to read a 50-word text, (2.) the time to perform a swing test by tenfold touching the moving fingertip of the examiner, and (3.) the amplitude of fusion were carried out.The results of these tests were further evaluated to test the hypothesis that impaired vision is significantly correlated to reduced cycling performances of alcoholised persons. In a second step, it was examined which test is most useful to identify alcohol intoxicated cyclists.The ophthalmologic examination results of the groups of best and worst cycling-performing test persons at blood alcohol levels between 0.10% and 0.15% were set into relation to the documented allocated demerits. Additionally, the individual results of these persons were compared to the state of soberness.The time needed to read a 50-word text significantly correlated with the cycling performance. As this is an easy and objective test, it might contribute to a synoptic evaluation of the psychophysical performance of a drunken cyclist.     

Evaluating alleged drinking after driving--the hip-flask defence. Part 2. Congener analysis

The second part of this review describes the principles and practice of forensic congener analysis as an alternative way to evaluate claims of drinking alcohol after driving. Congener analysis was developed, perfected and practised in Germany as a way to evaluate hip-flask defences. This kind of defence challenge arises frequently when the drunk driving suspect is not apprehended at the wheel and especially after hit-and-run incidents. Besides ethanol and water, alcoholic beverages contain trace amounts of many other low-molecular substances, known collectively as the congeners, which impart the characteristic smell and taste to the drink. Importantly, the congener profile can be used to identify a particular kind of alcoholic beverage. Forensic congener analysis entails making a qualitative and quantitative analysis of ethanol, methanol, n-propanol and the isomers of butanol in blood and urine from the apprehended driver and comparing the results with the known congener profile of the alcoholic beverage allegedly consumed after driving. Interpreting the results of congener analysis requires knowledge about the absorption, distribution and elimination pattern of the congener alcohols, including their oxidation and conjugation reactions, and any metabolic interactions with ethanol. Complications arise if drinks with widely different congener profiles are consumed or if the same beverage was ingested both before and after driving. Despite these limitations, congener analysis can furnish compelling evidence to challenge or support claims of drinking alcohol after driving.     

A formulation of cell surviving fraction after radiation exposure

Local energy transfer from electrons generated in biotissues that are exposed to ionizing radiation is fundamental to cell damage. Our aim in this investigation was to quantify the probability of cell mortality associated with the damage by electrons and the repair processes in the cell nucleus, envisaging a new interpretation of the cell surviving fraction (SF). We introduced a SF formula for cells exposed to X-rays, which is given as a linear combination of the Poisson distributions about the number of long-lived lesions per nucleus and their “non-lethal probabilities”, to show the non-linearity of log SF as a function of dose. The model selection was rated by a statistical index, Akaike’s information criterion (AIC). It was shown that the new formula is suitable for describing cell survival and explicitly takes account of the non-lethality in damage-processing pathways of the cells.     

Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging

RATIONALE AND OBJECTIVES: To assess in humans the pharmacokinetics of SonoVue, a new echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles and to provide additional safety and tolerability information on the compound. METHODS: The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination and laboratory parameters associated with the SonoVue injection. RESULTS: The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. CONCLUSIONS: SonoVue was shown to be rapidly removed from the blood. The route of SF6 elimination was by means of the lungs in the expired air. SonoVue appeared to be safe and well tolerated in healthy subjects.     

Comparison of 17-iodine-131 heptadecanoic acid kinetics from externally measured time-activity curves and from serial myocardial biopsies in an open-chest canine model

The relation between the externally measured myocardial time-activity curve and the radiochemically determined kinetics of iodine-131(131I) heptadecanoic acid was studied in an open-chest canine model under different metabolic interventions. Kinetics were assessed by analysis of 12 biopsies taken in an assay period of 90 min. Time-activity curves were fitted with a monoexponential plus constant. The halftime value of the exponential of the external curve corresponded well with the elimination rate of 131I from the myocardium: 14.6 +/- 4.5 min vs. 14.6 +/- 5.3 min. The constant was build up of three components: free 131I in cardiac tissue, the almost constant activity of the radiolabeled free fatty acid (FFA) in the myocardial lipid pool, and the radioactivity of blood and noncardiac tissues. The contribution of blood and noncardiac tissue to the constant amounted to a mean value of 77%. These findings support the analysis of externally measured time-activity curves with a monoexponential plus constant curve fit, in which background correction is not necessary. In cases where lipid storage is predominantly present, high T1/2 values, both internally and externally, were found, which were fitted with a monoexponential curve. It can be concluded that externally measured time-activity curves reflect satisfactorily the kinetics of radioiodinated heptadecanoic acid.     

The dose–response relationship for cancer incidence in a two-stage radiation carcinogenesis model incorporating cellular repopulation

Purpose : To investigate the role of cellular repopulation in the dose–response relationship for radiation carcinogenesis resulting from high doses of radiation. Method : A two-stage mathematical model of radiation carcinogenesis was developed and used to explore the effects of differing assumptions about repopulation by surviving normal stem cells and by one-stage mutants. Results : Characteristically, cancer incidence at any fixed time after irradiation increases with radiation dose, reaches a peak and then declines with dose (the decline reflecting radiation cell-killing). The optimal dose for cancer incidence, and the incidence level at this dose, are strongly influenced by repopulation kinetics. If repopulation does not occur, or is impaired owing to radiation damage to tissues, the highest value of cancer incidence is reduced, and this value occurs at a lower dose than if repopulation had been complete. A similar result is found if repopulation by one-stage mutants is impaired relative to unmutated cells, or if tissue recovery is assisted by immigration of unirradiated cells. Conclusions : Differing repopulation kinetics can account for differing dose–response relationships after large doses of radiation. These findings are relevant to the occurrence of ’second tumours? following radiotherapy and to the interaction of radiation with other agents.     

蓝萼香茶菜增加小鼠心肌血流灌注量的药效动力学

目的探讨蓝萼香茶菜药效动力学。方法以小鼠心肌血流灌注量为指标进行测定。结果蓝萼香茶菜在小鼠体内并非呈简单的房室模型,其最低起效剂量为生药0.7899 g.kg-1,效应达峰时间约为1 h,效应作用期长达6 h以上。结论蓝萼香茶菜体内具有吸收快,消除慢和作用维持时间长等特点。     

A study on the correlation of blood and vitreous humour alcohol levels in the late absorption and elimination phases

By using the urine:blood alcohol level ratio as the indicator, the correlation of blood alcohol level (B) and vitreous humour alcohol level (V) in the late absorption and elimination phases was studied. It was found to be good (r = 0.98) and B = 0.76V + 4.7. It is suggested that this equation can safely be used to estimate the minimum blood alcohol level where cadaveric blood is unsuitable or unavailable for analysis and that the B/V ratio can be used to infer the phase in which death occurred where urine is not available.     

Effect of restricted water exchange on cerebral blood flow values calculated with arterial spin tagging: a theoretical investigation.

Arterial spin tagging techniques originally used the one-compartment Kety model to describe the dynamics of tagged water in the brain. The work presented here develops a more realistic model that includes the contribution of tagged water in the capillary bed and accounts for the finite time required for water to diffuse across the blood-brain barrier. The new model was used to evaluate potential errors in cerebral blood flow values calculated using the one-compartment Kety model. The results predict that if the one-compartment Kety model is used to analyze arterial spin tagging data the observed grey matter cerebral blood flow values should be relatively insensitive to restricted diffusion of water across the capillary bed. For instance, the observed grey matter cerebral blood flow should closely approximate the true cerebral blood flow and not the product of the extraction fraction and the cerebral blood flow. This prediction is in agreement with recent experimental arterial spin tagging results.