Modeling Human Ethanol Metabolism

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Modeling Human Ethanol Metabolism

• (Or How I Learned to Stop Worrying and Love
  Applied Pharmacokinetics)

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Ethanol? Pharmacokinetics?!?

• Ethanol (ethyl alcohol) is produced in 2 ways
• As a petrochemical through the hydration of
  ethylene, most often used for industrial use.
• Biologically by fermenting sugars with yeast.
  This method yields organic fuel as well as
  alcoholic beverages (what we are interested in
  here).

C2H6O
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Ethanol? Pharmacokinetics?!?

• Pharmacokinetics is defined as the process by
  which a drug is absorbed, distributed,
  metabolized, and eliminated by the body.
  Wikipedia
• In particular, alcohol produces a dual effect on
  the body
• a primary depressant effect that lasts a
  relatively short time
• a weaker agitation of the central nervous system
  that persists about six times as long as the
  depressant effect
• There are some interesting aspects to the human
  bodys metabolism of ethanol that sets it apart
  from most other chemicals

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Why Model Ethanol Metabolism?

• Alcohol has been consumed by humans for various
  reasons for thousands of years. In some cultures
  it is part of day-to-day life.
• Due to its sense of euphoria and altered
  perception, alcohol consumption often comes into
  consideration in many legal situation and
  forensics.
• It is sexier than heat diffusion and wave
  mechanics combined.

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The Journey of Ethanol Through the Body

• Ethanol needs no digestion and is quickly
  absorbed by the body. About 20 is absorbed
  directly across the walls of an empty stomach and
  can reach the brain within one minute.
• It is then rapidly absorbed through the upper
  portion of the small intestine. From there it is
  carried through the blood to the liver.
  Eventually it ends up in the kidneys.
• Liver cells are the only cells that produce a
  worthwhile amount of the (dehydrogenase) enzyme
  that acts in breaking down alcohol.
  Interestingly, females produce less of this
  enzyme than males.

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The Journey of Ethanol Through the Body

• Ethanol is a neutral narcotic i.e. it
  penetrates rapidly through cells.
• Alcohol cannot gather to concentration in any
  particular organ or bodily fluid. As a whole it
  moves towards a diffusion equilibrium throughout
  the body.
• It is a water soluble narcotic (as opposed to a
  fat soluble narcotic such as cannabinoids). Thus,
  it is irrelevant how much fat a body contains in
  terms of metabolism.

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Approaches to Modeling Ethanol Metabolism

• The first widely accepted approach to modeling
  ethanol metabolism began around the beginning of
  the 20th century by Erik Matteo Prochet Widmark
  (1889 1945), a Swedish physiologist.
• Much of present-day modeling is still built upon
  his milestone book Principles and Applications of
  Medicolegal Alcohol Determination 1932.
• Widmarks work is so influential that in 1965 the
  University of Indiana set up the Widmark Award
  in his honor, which is presented at the
  International Conference on Alcohol, Drugs, and
  Traffic Safety (ICADTS).

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Widmarks Approach

• Widmark studied nearly every facet of alcohol
  pharmacology, including
• movement of ethyl alcohol into spinal fluid
• excretion of alcohol through breathing
• movement of alcohol from the mother to the embryo
• For uniformity, all experiments were done with
  the subjects stomach empty.
• Widmark believed that the overall most reasonable
  measurement was blood alcohol content (BAC) with
  units of grams of alcohol per 100 ml of blood.
  This is the standard today.

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Widmarks Approach

• Generalized alcohol conversion to mean
• all the processes through which a substance
  disappears from the body, whether through
  oxidation, elimination through the kidneys,
  exhalation through the lungs, or through
  chemical reactions
• Divided experimentation into 2 groups
• Conversion Independent of Concentration in Blood
• e.g. Methyl and Ethyl Alcohol
• Conversion Proportional to Concentration in Blood
• e.g. Acetone

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Widmarks Equation(s)

• Definition of terms
• ct concentration in blood at time t
• p body weight (in kilograms)
• r reduction factor, i.e. mass in which
  concentration of substance is equal to
  concentration of blood (gt pr reduced body
  mass)
• A total amount of substance administered (in
  grams)
• a total amount of substance in body at c
  concentration (in grams)
• B amount administered each time (for repeated
  doses, in grams)
• b amount given per unit time (in grams)
• t time (usually in minutes)
• T time in minutes between each repeated
  administration

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Widmarks Equation(s)

• Rate constants
• a drop in blood concentration per minute (when
  conversion is proportional to concentration)
• ß drop in blood concentration per minute (when
  conversion is independent of concentration)

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Widmarks Equation(s)

• r-value
• Known as Widmark constant, represents fraction of
  body mass where alcohol would be present if
  distributed at concentrations equal to that in
  blood
• Exact value heavily debated
• Widmark empirically derived values
• Males 0.68 - 0.085
• Females 0.55 - 0.055
• Values greater than 1.0 observed where r was not
  recorded under fasting conditions (presumably due
  to delayed alcohol absorption because of food)

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Widmarks Equation(s)

• General forms (conversion independent)
• Single Dose
• A r x p x C0 gt A pr (ct ß t)
  ct c0 - ßt
• Continuous Intake
• ct c0 (b / (pr) - ß )t
• What most modern equations are modeled after
• Intermittent Intake
• Curve through maxima of fluctuations
• a B ( (B / T ) - ß pr )t
• Curve through minima of fluctuations
• a ( (B / T ) - ß pr )t

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Widmarks Equation(s)

• Single Dose
• ct c0 - ßt

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Widmarks Equation(s)

• Continuous Intake
• ct c0 (b / (pr) - ß )t y represents c in
  graph

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Widmarks Equation(s)

• Intermittent Intake
• Curve through maxima of fluctuations a B (
  (B / T ) - ß pr )t
• Curve through minima of fluctuations a ( (B
  / T ) - ß pr )t

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Widmarks Equation(s)

• Most common modern generalization of Widmarks
  Equation is similar to
• where
• n drinks
• d oz. ethanol / drink
• w subject weight (in lbs.)
• B hourly decrease in ethanol
• (0.0514) lbs. ethanol / oz. Drink
• (1.055) g ethanol / mL
• r body mass containing alcohol (Widmark
  constant)

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Widmarks Results

• At any observable time, the alcohol content of
  the urine is consistently higher than that of the
  blood.
• People with higher percentage of body fat reach
  higher BACs faster after consuming an identical
  amount of alcohol than those with a lower
  percentage of fat.
• Rate of alcohol metabolism in humans is linear
  under most conditions (particularly at moderate
  BACs).

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Improving on WidmarkWatson, Watson, and Batt

• In 1981, Watson et al. published Prediction of
  Blood Alcohol Concentrations in Human Subjects.
  Updating the Widmark Equation in Journal of
  Studies on Alcohol.
• Primarily notion that the total body water (TBW)
  of a human being is crucial when trying to
  calculate BAC (comes into play in calculating
  Widmark constant value).
• Possibly second most important publication
  concerning alcohol pharmacology in the last 100
  years.

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Improving on WidmarkWatson, Watson, and Batt

• Believed that what value to give r can be
  entirely avoided by reducing the problem to
  first principles.
• Total body mass can be expressed as the sum of
  body fat mass and lean body mass.
• Lean body mass in turn can be expressed as total
  body water plus total lean solids mass (as
  Widmark noted, body fat mass is negligible).
• In any tissue, alcohol content is proportional to
  tissues water content.
• How to model TBW?

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Improving on WidmarkWatson, Watson, and Batt

• Watson et al. assumed elimination of alcohol
  follows zero-order kinetics (i.e. velocity of
  reaction independent of the concentration of
  substance).
• Let Bw (volume of water in blood) /
  (volume of blood)
• Alcohol can then be modeled by
• But how to model Bw and TBW?

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Improving on WidmarkWatson, Watson, and Batt

• Bw found to have a (uniform) mean of 0.80.
• Normal variations are relatively small.
• Through experimentation, linear regression
  equations relating TBW to age, height, and weight
  obtained.
• Designed to apply to any healthy Western adult
  population, from lean to obese.
• In women, age was not found to be a significant
  variable whereas in men it was.

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Improving on WidmarkWatson, Watson, and Batt

• Women TBW 0.1069h 0.2466w 2.097
• Men TBW 0.09516a 0.1704h 0.3362w
  2.447
• h height (in cm.)
• w weight (in kg.)
• a age (in years)

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Improving on WidmarkWatson, Watson, and Batt

• Compared results to Widmarks original method
• Found Widmarks method to overestimate BAC by 13
  mg per dl on average
• With a normal distribution about 0 (i.e. measured
  C0 value), subjects within of mean
• ATBW
• 35 people within - 5
• 63 people within - 10
• 83 people within - 15
• Widmark
• 17 people within - 5
• 31 people within - 10
• 50 people within - 15

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Improving on Widmark Forrests Method

• In 1986, A.R.W. Forrest improved upon Watson and
  outlined a procedure for determining TBW based
  upon body mass index (BMI).
• Assumed water proportion of bodys fat-free mass
  to be 72.4.
• Assumed water content of blood 80.
• One of few approaches that places significant
  emphasis (indirectly) on proportion of fat in the
  body.

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Improving on Widmark Forrests Method

• Equations

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Michaelis-Menton Kinetics Equation

• Biochemists Michaelis and Menton developed an
  equation to model enzyme kinetics.
• Potential use in modeling breakdown of ethanol by
  dehydrogenase.
• Particularly, can be used to improve upon rate
  that ethanol is eliminated from lean body mass.
• Now assuming first-order kinetics for alcohol
  elimination (i.e. reactionary velocity depends
  linearly on a single concentration).

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Michaelis-Menton Kinetics Equation
V1 catalyzed reaction Vmax maximum reaction
rate S concentration of substrate Km
Michaelis-Menton constant (based upon rate of
reaction)
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Current Models In Use

• Several general models employed by the Department
  of Transportation utilize an average blood
  alcohol curve to estimate ethanol elimination.
• Various pertinent factors (height, age, gender)
  are ignored.
• Many agencies use a machine that determines BAC
  based on percentage alcohol exhaled
  (breathalyzer).
• During conversion, alcohol moves across the
  membranes of the lung's air sacs (alveoli) and
  thus through surrounding air and into the breath.
• The ratio of breath alcohol to blood alcohol is
  21001.
• Pros
• Based upon readings from intoxicated individual
  as opposed to generalized curve.
• Much more convenient for field testing than blood
  or urine testing methods.
• Con
• Least reliable in terms of accuracy.

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Current Models In Use

• 3 major types of breath alcohol testing devices
• Breathalyzer
• Uses a chemical reaction involving alcohol that
  produces a color change
• Intoxilyzer
• Detects alcohol by infrared spectroscopy
• Alcosensor
• Detects a chemical reaction of alcohol in a fuel
  cell

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Current Models In Use

• Computer-based Models
• cBAC
• Addiction Research Foundation, Ontario, Canada
  1991
• Takes into account height, weight, age, gender,
  and TBW (but only for males)
• BACest
• NHTSA, Washington D.C, U.S.A. 1994
• Only uses weight and gender, but calculates
  separate TBW for men and women
• Both models found to significantly underestimate
  peak BAC level

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Possible Improvements to Model

• More recent implementations Pieters, et al.
  1990 have proposed a 3-compartment model
• stomach, small intestine, lean body mass
• Utilizes Michaelis-Menton Equation in relation to
  lean body mass.
• Adapt equations to increase granularity of
  computation.
• Develop more object-oriented approach to increase
  ease of use and logical correlation.
• Physiologically based model presented by Umulis,
  et al. 2004 moving towards this goal.

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The End

• Questions? Comments? Donations for further
  research?