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Biochemical and Physiological Research on the Disposition and Fate of Ethanol in the Body

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Garriott's Medicolegal Aspects of Alcohol, 5th edition, Edited by James Garriott PhD Lawyers & Judges Publishing Co., Tuscon, AZ, 2008 Chapter 3 Biochemical and Physiological Research on the Disposition and Fate of Ethanol in the Body A.W. Jones, Ph.D., D.Sc. Synopsis . Repetitive F Drinking 3.1 Introduction G. Effect of Age on Widmark Parameters 3.2 Fate of Drugs in the Body H. Blood-Alcohol Profiles after Drinking Beer 3.3 Forensic Science Aspects of Alcohol I. Retrograde Extrapolation 3.4 Ethyl Alcohol J. Massive Ingestion of Alcohol under Real-World Conditions A. Chemistry K. Effects of Drugs on Metabolism of Ethanol . B Amounts of Alcohol Consumed L. Elimination Rates Ethanol in Alcoholics During Detoxification C. Alcoholic Beverages M. Ethanol Metabolism in Pathological States . D Analysis of Ethanol in Body Fluids N. Short-Term Fluctuations in Blood-Alcohol Profiles E. Reporting Blood Alcohol Concentration . Intravenous O vs. Oral Route of Ethanol Administration . F Water Content of Biofluids 3.8 Ethanol in Body Fluids and Tissues 3.5 Alcohol in the Body A. Water Content of Specimens A. Endogenous Ethanol . Urine B . B Absorption 1. Diuresis 1. Uptake from the gut 2. Urine-blood ratios 2. Importance of gastric emptying 3. Concentration-time profiles 3. Inhalation of ethanol vapors C. Breath 4. Absorption through skin 1. Breath alcohol physiology 5. Concentration of ethanol in the beverage consumed 2. Blood-breath ratios C. Distribution 3. Concentration-time profiles 1. Arterial-venous differences . Saliva D 2. Plasma/blood and serum/blood ratios 1. Saliva production 3. Volume of distribution 2. Saliva-blood ratios . Metabolism D 3. Concentration-time profiles 1. Oxidative metabolism E. Cerebrospinal Fluid (CSF) 2. Hepatic alcohol dehydrogenase 1. Production and origin of CSF 3. Inhibition of alcohol dehydrogenase 2. Concentration-time profiles 4. Gastric alcohol dehydrogenase . F Tears 5. Hepatic aldehyde dehydrogenase G. Sweat 6. Microsomal oxidative enzymes CYP2E1 H. Mother’s Milk 7. Non-oxidative metabolism of ethanol I. Brain and Body Organs 3.6 Pharmacokinetics of Ethanol J. Vitreous Humor A. First-Order Kinetics K. Hair . Zero-Order B Kinetics 3.9 Concluding Remarks C. Non-Linear Saturation Kinetics References . D The Widmark Equation E. Updating the Widmark Equation 1. Body mass index 2. Total body water 3.1 Introduction . Pharmacokinetics F of Ethanol Metabolites Few if any drugs have been studied as extensively and over G. Physiological Range of Ethanol Elimination Rates so many years as ethanol or ethyl alcohol (CH CH OH), the 3.7 Characteristics of Blood-Alcohol Curves 3 2 A. Ingestion of Alcohol on an Empty Stomach principal psychoactive substance in all alcoholic beverages. Inter- B and Intra-Individual Variations Much has already been written and published about the ab- C. Factors Influencing C and t max max sorption, distribution and metabolism of man’s favourite D. Effects of Food in the Stomach E. Gender Differences drug, both from the viewpoint of forensic science and legal 47 48 Garriott’s Medicolegal Aspects of Alcohol medicine as well as substance abuse and biomedical alcohol cesses (Benet et al., 1990; Kalant et al., 2006; Waller et al., research. Knowledge about the disposition and fate of ethanol 2005). Knowledge about the disposition and fate of ethanol in the body is important in forensic science and toxicology be- in the body predates that of all other drugs and xenobiotics cause of the role played by over-consumption of alcohol and thanks mainly to the early availability of a reliable method drunkenness in many crimes of violence, sudden deaths and for quantitative analysis of ethanol in small volumes of blood particularly in connection with police investigations of drunk- (Widmark, 1922). This involved a micro-diffusion method, en driving (Doll et al., 1994; Hume and Fitzgerald, 1983). which utilized only 100 µL of fingertip capillary blood, thus Historically, the first scientific efforts to interpret blood making it possible to take repetitive blood samples and to alcohol concentration (BAC) in relation to the quantities plot the concentration-time profiles of ethanol (Widmark, consumed and the detrimental effects on body functioning 1922; Widmark, 1932). can be traced to the pioneer work and publications of Pro- The word pharmacokinetics was coined in 1953 by a fessor Erik MP Widmark (1889-1945) of Sweden (Widmark, German scientist Friedrich Hartmut Dost (1910-1985) and 1920). Widmark’s research was done during the 1920-1930s is concerned with the way that drugs and their metabolites and was summarized in his famous German monograph, are absorbed, distributed and eliminated from the body which first appeared in print in 1932 and was translated into and representation of these processes in quantitative terms English 50 years later (Widmark, 1932; Widmark, 1981; (Dost, 1953; Gabrielsson and Weiner, 2000; Wagner, 1993). Andréasson and Jones, 1996). Kinetics comes from the Greek word kinesis, which means Information about the absorption, distribution, metabo- motion; so pharmacokinetics has to do with the movement lism and excretion of ethanol can be obtained from various or time-course of a drug (Greek=pharmacon) in the body textbooks and periodicals devoted to biomedical alcohol re- (Kalant et al., 2006; Wagner, 1991). Monitoring the concen- search (Wilkinson, 1980; Von Wartburg, 1989; Batt, 1989; tration (or amount) of a drug in blood or other body fluid Kalant, 1996b; Lands, 1998; Matsumoto and Fukui, 2002; and showing how the concentrations change as a function Ramachandani et al., 2001b). The articles by Kalant (1971; of time forms the basis of clinical pharmacokinetics and 1996b; 2005) are particularly useful and give a detailed in- therapeutic drug monitoring (Greenblatt and Koch-Weser, sight into the uptake, distribution and elimination of alcohol 1975a,b; Rowland and Tozer, 1995). in the human body. Comprehensive Handbook of Alcohol Related Pathology was the title of a three volume set of books edited by Preedy and Watson (2005). This handbook contained an impressive compilation of information on all aspects of biomedical alcohol research. Journals specializ- ing in clinical pharmacology and toxicology occasionally publish articles dealing with the metabolism and pharma- cokinetics of ethanol and adverse drug-alcohol interactions of interest in certain forensic investigations (Holford, 1987; Fraser, 1997; Norberg et al., 2003). The present chapter combines and updates two separate chapters published in the fourth edition of “Medical-Legal Aspects of Alcohol.” One chapter dealt with biochemistry and physiology of ethanol metabolism (Jones 2003a) and the other covered the basic principles and concepts underly- ing studies on the disposition and fate of ethanol in the body (Jones, 2003b). 3.2 Fate of Drugs in the Body Disposition relates to what happens to a drug after it enters Figure 3.1 Definitions and distinction between the body and therefore starts with absorption and other pre- pharmacokinetics and pharmacodynamics, both of systemic processes followed by the events occurring after which are key concepts in studies of the disposition the drug enters the blood circulation, particularly its distri- and fate of drugs in the body. bution and elimination via metabolism and excretion pro- 3. Disposition and Fate of Ethanol in the Body 49 The subject of pharmacodynamics is concerned with ments raised during the prosecution and defense of drunken the physiological effects of drugs and their mechanism of drivers (Gullberg, 2004; Jones, 1991b; Breen et al., 1998; action in the body (Buxton, 2006). This entails investiga- Wigmore and Wilkie, 2002). tions of how a drug treatment influences normal body func- The science and law of drunken-driving litigation has tioning or results in a change in performance and behavior been extensively covered from the perspective of legislation of the patient. Dose-response and concentration-effect rela- in the United States (Erwin, 1991; Cohen and Green, 1995; tionships, risk of toxicity and overdose and the development Fitzgerald, 2006; Bartell and Imobersteg, 2007). These of tolerance and dependence also fall under the rubric of books often run into several volumes and include regular pharmacodynamics (Ross, 1990; Buxton, 2006). The terms, updates and supplements dwelling on the interface between pharmacokinetics and pharmacodynamics, are defined and science and law. The target readers are mainly lawyers and distinguished in Figure 3.1. Detailed knowledge of the dy- law firms that specialize in defending drunken drivers and namics of drug action is of major importance for a proper therefore need to be kept abreast of developments in case understanding of the forensic pharmacology of ethanol and law as well as the pros and cons of a multitude of science- other abused drugs. related defense arguments (Lewis, 1986b; Jones, 1991b; Ferner and Norman, 1996; Langford et al., 1999; Gullberg, 3.3 Forensic Science Aspects of Alcohol 2004). Books by Rockerbie (1999) and Drummer (2001) Medical and legal aspects of alcohol, which are the subjects also focused on the forensic pharmacology of ethanol and of this book, are closely related to excessive use of alco- other abused drugs. hol and the many negative consequences associated with Forensic alcohol research has developed alongside binge drinking and drunkenness (Brewer and Swahn, 2005; biomedical alcohol research and is tightly linked to the dis- MacMillan and Wathen, 2005; Cherpitel, 2007). A person’s position and fate of alcohol in the body and the analytical ability to perform skilled tasks, such as driving a motor ve- methods used to determine ethanol in body fluids such as hicle safely, is compromised as blood alcohol concentration blood, plasma, breath, saliva and urine (Jones, 2000a; Jones, increases (Hindmarch et al., 1992). Road traffic crash sta- 2006). Some studies are undertaken for the sole purpose of tistics show that 30-50% of all deaths on the roads in U.S. evaluating the strengths and weaknesses of a plethora of de- states and European nations are alcohol-related and involve fense arguments raised to cast a doubt on evidence used dur- a drunken driver (Voas et al., 2006).
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