Download Pharmacodynamics and Pharmacokinetics of Alcohol

Pharmacodynamics and
Pharmacokinetics of Alcohol
A.W. Jones, PhD, DSc
Department of Forensic Toxicology, University
Hospital, 581 85 Linköping, Sweden.
[email protected]
Presented at meeting of the California Association of
Toxicologists, Santa Rosa, CA, 1-2 August, 2003.
Pharmacokinetics
Studies of the movement of drugs
into, within and out of the body
What the body does to the drug
CH3CH2OH
Pharmacodynamics
Studies of the effect and mechanism
of action of drugs on the body
What the drug does to the body
Pharmacokinetics
Pharmakon = drug or poison
Kinesis = movement
The discipline known as pharmacokinetics
deals with the way that drugs and their
metabolites are absorbed, distributed, and
eliminated in the body and how these
processes can be described in quantitative
terms.
Pharmacokinetics of ethanol
• Forensic pharmacokinetics
– Widmark’s model
• One-compartment, zero-order elimination
– Michaelis-Menten elimination
• Saturable kinetics – dose dependent
• First-order kinetics
– Operates at very low & perhaps at very high BAC?
• Multicompartment models
– Arterial and venous blood compartments
• Physiologically-based kinetic models
– PB-PK
• Population kinetics
Forensic Pharmacokinetics
Peak
BAC
Blood Ethanol, mg/dl
150
Drinking
Spree
Rise in
BAC
100
50
Time
to
Peak
β -slope
0
0
30
60
90
120
150
180
210
240
Time After Start of Drinking, min
270
300
Pharmacokinetic Models
V
Dose
ko
Dose
C
1.2
km
C
Vmax
1.2
1
1
Blood Ethanol, g/L
Blood Ethanol, g/L
V
0.8
0.6
0.4
0.2
0.8
0.6
0.4
0.2
0
0
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
Time, h
-dc/dt = ko
Ct = Co - kot
Time, h
-dc/dt =
Vmax x C
km + C
Response feature analysis of BAC
profiles - noncompartmental analysis
200
Blood Ethanol, mg/dl
Peak BAC
Typical curve after
intravenous Infusion
150
Diffusion plunge
100
β -slope = Co/Mino
Co
50
First-order kinetics
AUC
Mino
0
0
100
200
300
400
500
600
Time After Start of Infusion, min
700
Important articles on EtOH kinetics
• Widmark
– Principles and application of medicolegal alcohol
determination. Biomedical Publications, Foster City, CA,
1981 (tanslation of Widmark’s 1932 German monograph)
• Lundquist & Wolthers
– Acta Pharmacol & Toxicol 1956;14:265-289.
• First application of Michaelis-Menten kinetics, thanks to use of
more sensitive enzymatic ADH method for blood-alcohol analysis
• VonWartburg
– Chapter in ”Human metabolism of alcohol” (vol 1, Crow
and Batt, editors) CRC Press, 1989, pp 9-22.
• Comprehensive review of ethanol pharmacokinetics as well as
applications in forensic casework.
Important articles on EtOH kinetics
• Wilkinson
– Alcohol. Clin. Exp. Res. 1980;4:6-21.
• Comprehensive review of ethanol pharmacokinetics with emphasis
on Michaelis-Menten equation.
• Holford
– Clin. Pharmacokinet. 1987;13:273-292
• Comprehensive review of clinical pharmacokinetics of ethanol
• Kalant
– Chapter in ”Pharmacology of alcohol and alcohol
dependence” (Begleiter & Kissin, editors) Oxford
University Press, 1996, pp 15-58.
• Norberg et al
– Clin. Pharmacokinet. 2003;42:1-31
• Comprehensive review of clinical pharmacokinetics of ethanol
with focus on variability and forensic issues.
Properties of the Drug
Ethyl Alcohol CH33CH22OH
• Small molecule (MW 46.05).
• Unionized at physiological pH and carries
only a weak charge
• Dosage form (beer, wine, spirits).
• Easily passes biological membranes.
– Including blood-brain barrier
• Completely miscible with water.
• Low solubility in lipids and bone.
• Negligible binding to plasma proteins.
Analytical Considerations
• Choice of biofluid for analysis
– blood, plasma, urine, saliva, breath
• Different kinetic parameters Vd ko and t½
• Sampling variations
– Pre-analytical factors
• Sampling site, technique, transport, storage, stability,
preservatives?
• Choice of method of analysis
– Enzymatic (ADH) or gas chromatoraphy
– Calibration standards
• External controls, tracability?
– Headspace gas chromatography currently
considered gold standard method
Precision, Accuracy, Specificity
Within laboratory precision 0.5-1.5% CV
Between Laboratory Variation
• Forensic Labs*
• Clinical Chemistry Labs
CV = 2-3%
CV = 6-9%
* Laboratories specializing in blood-ethanol assays and
using standardized routines based on headspace GC and
internal standard, etc.
Use of breath-alcohol analyzers
Seemingly increasing (non-invasive)
• Breath-alcohol concentration
follows arterial and not venous
blood-alcohol concentration.
• The venous blood-breath ratio of
alcohol is a moving target.
• What blood/breath factor was
used for calibration?
– Details rarely given.
• Results depend on pre-exhalation
pattern.
Screening device
for police use
Pharmacodynamics
Studies of biochemical and
physiological effects of drugs on
living organisms including
mechanisms of action, dose response
relationships, and drug-effects on
behavior in relation to chemical
structure and dosage form.
Pharmacodynamics of ethanol
• How EtOH drinking influences the behavior
and the actions of an individual
– Metabolic effects
• Metabolism of ethanol produces energy 7.1 kcal per g
– Central Nervous System (CNS) effects
– Ethanol as a psychotropic drug
– Impairment of performance and behavior
• Mechanisms of action
– Intermediary metabolism
– Cell membranes
– Receptor sites and ion channels
Can EtOH be compared with inhaled anesthetics?
Hydrocarbons &
chlorocarbons
Ethers
Diethylether
Ethylene
Chloroform
Others
Cyclopropane
N2O
Xe
Halothane
Enflurane
Methoxyflurane
Isoflurane
Servoflurane
Mechanism of anesthesia
Lipid solubility (Meyer-Overton correlation)
Disruption of lipid bilayer
Interaction with specific receptors (GABA, NMDA)
The Cell Membrane
Meyer-Overton observed that the potencies of
anesthetic drugs are directly proportional to their lipid
solubilities - disrups lipid portion of cell membrane.
Muscle
Relaxant
Benzodiazepines
Anticonvulsant
CH3
O
N
Cl
Anxiolytic
N
Diazepam
Sedative
Hypnotic
BAC vs Effects close to peak concentration
BAC [%]
Effects of alcohol on the individual
0.02-0.03
Mood elevation. Slight muscle relaxation.
0.05-0.06
Feelings of relaxation and warmth. Increased reaction
time. Decreased fine muscle coordination.
0.08-0.09
Impaired balance, speech, vision, hearing, muscle
coordination. Marked euphoria.
0.14-0.15
Gross impairment of physical and mental control.
0.20-0.30
Severely intoxicated loss of control of mind and body.
0.40-0.50
Unconscious. Deep coma. Death from respiratory
depression.
Alcohol Dose 1.25 g/kg
(277 mL or 9.2 oz whisky/70 kg man)
10
8
BAC 110 mg/dL
150
6
100
4
Intoxication
Score
50
2
0
0
0
Alha, 1951
1
2
3
4
Time After Drinking, h
5
6
Intoxication Score (symptoms)
Blood Alcohol mg/dl
200
Suspected drunk drivers (N = 1453) apprehended by
the police and examined by different physicians who
concluded they were not under the influence of alcohol
BAC, g%
0.00-0.049
Number of
cases
431
Percent not
under influence
30%
0.05-0.099
441
30%
0.10-0.149
360
25%
0.15-0.159
161
11%
0.20-0.249
51
3.5%
0.25-0.299
10
0.7%
Suspected drunk drivers (N= 244) apprehended by the
police and examined by the same physician to assess
whether they were under the influence of alcohol.
BAC g%
Number
No
Slightly Moderatly Severly
0.00-0.049
29
39
54
47
47
25
3
3
2
2
1
-
26
37
41
24
20
7
1
0.05-0.099
0.10-0.149
0.15-0.199
0.20-0.249
0.25-0.299
0.30-0.349
10
17
22
11
1
1
5
5
7
1
Altered synaptic activity caused by ethanol
working at multiple molecular sites
• Neurotransmitter systems
–
–
–
–
Dopamine (5HT3) - excitatory
GABAA - inhibitory
Glycine - inhibitory
Glutamate (NMDA)* - excitatory
• Excitation & dependence
• Dopamine, 5HT3
• Sedation and intoxicating
effects
• GABA, glycine, glutamate
• No known antagonist of EtOH
seemingly exists
• RO15-4513 had some potential
* N-methyl-D-aspartate receptor
Receptors involved in some of the actions of ethanol
Effects on ligand-gated ion channels
GABAA inhibitory receptor EtOH
potentiates the effect of GABA
GABA Receptor
Benzodiazepine
receptor
Barbiturate
receptor
Chloride
channel
Effects of Ethanol on the Brain
Alcohol is not evenly
distributed in the brain.
Concentrations depend on
blood flow and water
content.
•
Impairment of cognitive and
psychomotor functions
•
First emotion and decision making
e.g. reasoning, thinking, learning
and judgement
•
Next muscular control e.g.marked
impairment of movement, balance,
speech, reaction time etc.
•
Last affected is respiration and
circulation (v. high BAC).
•
Degree of impairment depends on
dose, rate of drinking and prior
experience with alcohol
Tolerance
Acute Tolerance
• From studies mainly in dogs, Mellanby found
that the degree of impairment to alcohol was
greater at a given blood-alcohol concentration
on the rising portion of the blood-alcohol curve
than it was at the same concentration on the
descending part of the curve.
– Some toxicologists considered that the Mellanby effect
was caused by the different alcohol concentration in
arterial blood reaching the brain and the venous blood
returning from muscle tissue, which was assumed to be
the specimen analyzed.
Widmark’s definitions
• Consumption Tolerance
– For a given consumption of alcohol, different blood alcohol
concentrations are reached for different individuals.
• This depends on different patterns of absorption, distribution
and elimination and body composition.
• Concentration Tolerance
– This relates to the concentration of alcohol in blood causing
effects on the individual. The intensity of these symptoms
differs between individuals at the same blood-alcohol
concentration.
• The mechanism of concentration tolerance relates to the
effects of alcohol on the brain – acute and chronic tolerance.
Tolerance
• Dispositional Tolerance
– Changes in absorption, distribution, excretion and
metabolism of the drug which might lead to a
reduction in intensity and duration of the effects
on the individual.
• Functional Tolerance
– Changes in sensitivity of the brain or other tissue
making it less sensitive to the same degree of
exposure to the drug.
Definitions given by Dr. Harald Kalant, Toronto.
Pharmacological Reviews 23;1971, pp 135-191.
Alcohol in the Body
• Absorption phase
• Distribution phase
• Elimination phase
– Metabolism
• Oxidation & conjugation
– Excretion
Rate of Absorption
• Depends on many factors
– Route of administration
• Inhalation, sub- and per-cutaneously,
intravenously, rectally, perorally.
– Dosage form
• Beer, wine, distilled spirits
• Dilution and CO2 content
• Buffer capacity
– Gastric emptying
• Food, time of day, blood-glucose
1.2
Esophagus
Pyloric
sphincter
Blood Ethanol, g/L
1
0.8
0.6
0.4
0.2
Slow
absorption
across
stomach
wall
0
0 1 2 3 4 5 6 7 8
Time, h
1.2
1
Blood Ethanol, g/L
Rapid absorption from
duodenum
Slow gastric
emptying
0.8
Rapid
gastric
emptying
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8
Time, h
Critical Role of Stomach
Emptying on Peak BAC
• Man 80 kg, drank 190 ml whisky
over 60 min, venous BAC at 5.35
p.m. was 0.052 g%
• Man 88 kg, drank 190 ml whisky
over 60 min venous BAC at 5.50
p.m. was 0.011 g%
• Man 75 kg, drank 190 ml whisky
over 60 min venous BAC at 5.46
p.m. was 0.049 g%
Pyloric
Sphincter
Distribution phase
• Depends on many factors;
– Water content of the various fluids and
tissues
• More H20 more alcohol.
– Importance of ratio of blood flow (F) to
tissue mass (M).
• Low ratio F/M large A-V difference
– Body water depends on age, gender and the
proportion of fat to lean tissue (obesity).
– Widmark’s rho-factor
Measuring Total Body Water
! Isotope dilution methods
! Water labelled with deuterium
! Water labelled with tritium
! H2O18
! Ethanol dilution
! Bioelectrical impedance measurements
! Anthropometric measurements
! Age, weight, and height
! Weight/height2 (kg/m2) body mass index
Widmark’s experimental conditions
1.
Twenty healthy men and ten healthy women all of
whom were moderate drinkers.
2. Rapid ingestion of spirits (30-40% v/v) in a single
moderate dose (0.5-0.9 g/kg) on an empty
stomach (overnight fast).
3. Sampling and analysis of fingertip capillary blood
at 30-60 min intervals for 6-7 hours.
4. Reporting concentrations of ethanol in mg
ethanol per gram blood (not per mL).
1.
Average rho men 0.68, rho women 0.55
2. Average ß men 0.15, ß women 0.16
Watson, Watson and Batt
J. Stud. Alcohol 42;547-556, 1981
! They derived multiple regression equations to
express the relationship between TBW and a
persons age, gender, height, and weight.
! For men the height was not so important for
the calculation of TBW.
! For women neither age nor height were
seeminly vital for calculation of TBW.
Anthropometric Measurements
• Healthy Men
– TBW = 20.03 - 0.1183 yr + 0.3626 kg
• Male 32 y, 65 kg, TBW = 39.8 L (61.2%)
• Standard deviation 3.86 liters (CV = 9.7%)
• Healthy Women
– TBW = 14.46 + 0.2549 kg
• Female 65 kg, TBW = 31.0 L (47.7%)
• Standard deviation 3.72 Liters (CV = 12%)
• Rho-factor = (water in body)/(water in blood)
• Blood water = 82-85 % w/v
Estimating Total Body Water (TBW) by the Ethanol
Dilution Method
! Conditions*
p.o. Fasting
(0.68 g/kg)
20-29 y
30-39 y
40-49 y
44.2 L
47.8 L
(60.2%) (59.1%)
Anthropometric 44.4 L
data**
(60.8%)
45.6 L
(56.5%)
Infusion of ethanol (0.6 g/kg)
Anthropometric data**
50-59 y
47.9 L 46.5 L
(56.7%) (55.3%)
46.5 L
(55.1%)
TBW
TBW
45.3 L
(53.9%)
40.3 L (50.1%)
42.1 L (52.9%)
Men aged 62 y (span 55-68 y)
* N = 12 men per age group. * * Watson, Watson, Batt.
Recent Update of Widmark’s rho Factor
! Widmark rho for men
! 0.31608 – 0.004821 weight (kg) + 0.004632
height (cm)
! Widmark’s rho for women
! 0.31223 – 0.006446 weight (kg) + 0.004466
height (cm)
! These equations were evaluated in
controlled drinking experiments.
Seidel et al, Int. J. Legal Med.114;71-77, 2000
Elimination process
• Metabolism + excretion
– Metabolism - oxidation
• Various enzyme systems involved
– ADH, ALDH, CYP2E1, Catalase?
• Conjugation
– Ethyl glucuronide
– Excretion
• Passive diffusion
– Breath, Sweat, Urine
Organs
Absorption
phase
Hepatic
metabolism
First pass
metabolism
Phase I enzymes
Phase II enzymes
Excretion
processes
Urine
Breath
First-Pass Metabolism
Oral Dose
Class
IV ADH
Gut
Class I
ADH
Liver
Sampling Compartment
I.V. administration sidesteps problems
with first-pass metabolism
First-Pass Metabolism
! Defined as the loss of drug as it
passes through the gastro-intestinal
membranes and the liver, for the
first time, during the absorption
process
Much research has focused on the role of alcohol
dehydrogenase located in the gastric mucosa, so
called gastric ADH (Class IV) as site of first-pass
metabolism with a high km for ethanol oxidation.
age
sex
race
body
mass
index
Dose
State of
health;
liver
kidney
gut
The
Individual
The
Environment
Concentration of
Ethanol in Blood
Pathophysiology
Genetics and
genomics
smoking
drinking
food
drugs
Speed of
drinking
Activity of
hepatic
enzymes
polymorphism
Inter-individual Variations
Alcohol and aldehyde dehydrogenase enzymes
Methanol
Alcoholdehydrogenase
(ADH)
NAD+
Ethanol
Formaldehyde
NADH
Aldehydedehydrogenase
(ALDH)
NAD+
Acetaldehyde
ADH1
ADH2*1, ADH2*2, ADH2*3
ADH3*1, ADH3*2
Located in cytosol
Formate
NADH
Acetate
ALDH1
ALDH2*1, ALDH2*2
Located in mitochondria
Intra-individual Variations
Intra-individual variations
Male Subject 23 y
40 g ethanol in 5 min
empty stomach
Blood Alcohol mg/g
1.0
0.8
N = 10 experiments
During 9 weeks
β = 0.157 mg/g/h
(range 0.14 - 0.20)
0.6
0.4
0.2
0
0
100
200
Time after bolus intake, min
300
Intra-individual variations in EtOH
elimination rate from blood
N = 12 male subjects
consumed EtOH 0.8 g
per kg body weight on
4 occasions after an
overnight fast.
Elimination rate β-slope g/dl/h
0.020
0.015
0.010
Mean value of ß-slope
0.0142 g%/h, range
0.0117-0.0173 g%/h
0.005
0.00
1
2
3
Alcohol Drinking Session
BJCP 35;427-431, 1994
4
Inter- vs intraindividual variation
not significantly
different by ANOVA
Conjugation
ethyl glucuronide
< 1%
Ethanol
CYP2E1
microsomes
~10%
Chemically
reactive
3-5%
ADH
Excretion
breath, urine,
sweat
cytosol
~85%
Acetaldehyde
Toxic
metabolite
ALDH
mitochondria
H2 O
Acetate
coenzyme A
CO2
Breath
Urine
Sweat
~5%
CH3CH2OH
NAD+
H+ + NADH
~0.1%
~94%
Alcohol
Dehydrogenase
(ADH)
Ethyl
glucuronide
EtOH
> 0.06 g%
CH3CHO
NAD+
Aldehyde
Dehydrogenase
(ALDH)
CYP2E1
H+ + NADH
CH3COOH
CO2
CH3CHO
H2O
Metabolic disturbances during hepatic
oxidation of ethanol
• Altered hepatic redox state owing to increae in
the NADH/NAD+ ratio means;
– Pyruvate is converted to lactate which competes with
ureate for excretion via kidney and results in uric acid
accumulation and gout and lactacidosis.
– Hepatic synthesis of glucose is impaired
• hypoglycemia
– Reduced citric acid cycle (excess acetyl CoA)
– Promotion of fatty acid synthesis
• Risk for ketoacidosis
– Reduced lipid oxidation
• Accumulation of fat in hepatocytes.
Long-term effects of chronic heavy drinking
on the liver
Fatty liver, hepatitis and fibrosis are intermediate
stages, although these are reversible.
Healthy liver removed
at autopsy
Cirrhotic (orange) liver
removed at autopsy
Drug-Alcohol Interactions
• Pharmacokinetic (metabolic) Interactions
– Effects on absorption, distribution, elimination
• Acute vs chronic intake – metabolic tolerance?
• Competition for metabolizing enzymes (CYP450)
• Influence on stomach emptying
• Pharmacodynamic Interactions
– Acute vs chronic intake – CNS tolerance?
– Synaptic activity
• binding to receptor sites, opening of ion channels
Alcoholdehydrogenase
Methanol
Aldehydedehydrogenase
Formaldehyde
NAD+
NADH
Ethanol
NAD+
Formate
NADH
Acetaldehyde
Acetate
Alcoholdehydrogenase
Aldehydedehydrogenase
Blocked by
4-methyl pyrazole
Blocked by
Disulfiram
fomepizole (Antizol®)
Antabuse®
Drug alcohol metabolic interactions
at specific enzymes
• Alcohol dehydrogenase
– 4-methyl pyrazole, other alcohols,
chloral hydrate
• Aldehyde dehydrogenase
– Disulfiram, calcium carbimide,
• CYP2E1
– Acetaminophene, chlormethiazole
• Drugs used in treatment of stomach problems
– Histamine-H2-antagonists inhibitors of gastric ADH?
• Cimetidine (Tagamet®)
• Ranitidine (Zantac®)
– Proton-pump inhibitors
• Omeprazole (Losec®)
H
N
H3C
NCN
Histamine
H
N
N
CH3NHCNHCH2CH2SCH2
N
NH 2CH 2CH 2
Cimetidine (Tagamet®)
H
4-methyl pyrazole
Fomepizole Antizol®
H 3C
N
N
Jönsson et al. Eur J Clin Pharmacol
42;209-12, 1992
(A)
25
20
15
10
A = Cimetidine 7 days
B = Ranitidine 7 days
C = Omeprazole 7 days
compared with no-drug
treatment, EtOH 0.8 g/kg
-1
Blood Ethanol (mmol l )
5
0
(B)
25
20
15
10
5
0
(C)
25
20
15
10
5
0
0
1
2
3
4
Time (h)
5
6
Many studies used very small
doses of alcohol e.g. 0.150.30 g/kg and found small
increases in peak BAC
0.008-0.015 g/100 mL
Moderate Drinker
Drug
CYP450
+ EtOH
X
Drug
Metabolites
Heavy Drinker
Drug
Activated
CYP450
Drug
Metabolites
X
Prolonged
Therapeutic
Effect of the
Drug
Diminished
Therapeutic
Effect of the
Drug
Sulfate
conjugate
~35%
Glucuronide
conjugate
~60%
Acetaminophene
CYP2E1
~5%
Induced by alcohol,
fasting, protein deficiency
N-acetyl-p-benzoquinone imine
(NAPQI)
Reactive
intermediate
Glutathione
inactivation
Glutathione
conjugate
Covalent binding to
tissues – cell death
Hepatotoxicity
Toxicity of Ethanol
Some Factors to Consider
•
•
•
•
•
•
Age, gender, body mass index
Dose, beverage type, speed of drinking
Route of administration
Hypothermia
Development of chronic tolerance
General state of health
– Malnutrition, metabolic disorders, ketoacidosis
• Concomittant use of other drugs
– CNS depressants
– Opiates
• Evidence of positional asphyxia or inhalation
of vomit.
At what blood-concentration
does alcohol kill?
Different authorities cite different
concentrations derived presumably from
personal experiences but where is the
documentation?
Bernard Knight (UK) >0.30 g%
DiMaio & DiMaio (USA) 0.40 g%
We recently looked at all deaths in Sweden
attributed to acute alcohol poisoning with alcohol
as the only drug present in femoral venous blood
Gender
N
Blood
Alcohol
Mean
Age
Male
529
0.355 g%
54 y
Female
164
0.373 g%
53 y
Jones and Holmgren, J. Forensic
Sciences (USA), July 2003
Deaths Ascribed to Acute Alcohol Poisoning
250
250
Normal
200
Frequency
Acute Alcohol
Poisoning Deaths
N = 693
Mean 0.36 g/100 mL
Median 0.36 g/100 mL
200
150
150
100
100
50
50
0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Blood-Ethanol Concentration, g/100 mL
0
0.7
Deaths Ascribed to Chronic Alcoholism
Frequency (%)
30
30
Indications
N = 703
Mean 1.70 g/L
Median 1.50 g/L
Range 0.1 to 5.6 g/L
20
20
10
10
0
0.0
1.0
2.0
3.0
4.0
5.0
0
6.0
Blood-Ethanol Concentration, g/L
•
•
•
•
•
•
•
•
Fatty Liver
Hepatitis
Cirrhosis
Pancreatitis
Cardiomyopathy
Ascites
Psychoses
Ketoacidosis
Drunk drivers in Sweden with very high
blood-ethanol conc., > 0.4 g% (N = 120)*
Gender (body
weight)
N (%)
Mean
BAC g%
EtOH in
body, g
5 h**
metabolism
Male (75 kg)
107 (89%)
0.428
225 g (710
mL vodka)
265 g (810
mL vodka)
0.435
159 g (530
mL vodka)
199 g (570
mL vodka)
Female (65 kg) 13 (11%)
* Swedish records (0.545, 0.544, 0.518, 0.505, g%)
** 8 g/h = 40 g = ~100 mL spirits
Physiological range of ethanol
elimination rates from blood
BAC rate of
Conditions or treatment
decline g% per h
0.08-0.010
People with liver dysfunction (e.g. cirrhosis) or those who
are malnourished, eat low-protein diets or take a drug that
blocks ADH e.g. fomepizole (4-methyl pyrazole)
0.010-0.013
Healthy people who drink moderate amounts of alcohol
after an overnight fast.
0.013-0.016
Healthy people who drink moderate dose of ethanol under
non-fasting conditions.
0.016-0.025
Heavy drinkers such as drunk drivers who reach
appreciably high BAC (> 0.12 g/100 mL)
0.025-0.035
Alcoholics during detoxification or binge drinkers
immediately after heavy drinking. Treatment with protein
or amino acid rich diets or those suffering from conditions
leading to a hypermetabolic state.
t1
t2
Time
Blood Alcohol Conc.
Blood Alcohol Conc.
Rate of ethanol elimination in drinking
drivers?
t1
Time
Assuming post-absorptive phase and zero order kinetics
J. Forensic Sci. Vol 41, 922-926, 1996.
Example of calculating elimination rates
based on double blood samples
Case
(blood)
1a
Time BAC g% Pair of
of day
bloods
20.39 0.248
1a_1b
BAC rate of
decline g%/h
0.019
1b
21.42 0.228
1a_1c
0.020
1c
22.05 0.220
1b_1c
0.021
2a
05.55 0.217
2a_2b
0.021
2b
06.15 0.210
2a_2c
0.020
2c
07.35 0.183
2b_2c
0.020
ß-Slope as a Function of Age in
Male and Female DWI Suspects
Blood-Alcohol Decay Rate,
mg/ml/h
0.30
0.30
Women
Men
0.25
0.25
0.20
0.20
0.15
0.15
0.10
0.10
0.05
0.05
0.00
<20y
20-29y
30-39y
40-49y
Age
50-59y
>60y
0.00
Frequency
Ethanol elimination rate in DWI suspects
250
250
200
200
Derived from double
blood samples
• Mean 0.019 g% per h
150
150
100
100
50
50
• SD 0.005 g% per h
• Median 0.019 g% per h
• Min 0.00 g% per h
• Max 0.046 g% per h
0
0.00
0.01
0.02
0.03
0.04
0
0.05
Elimination Rate, g/100 mL per h
• 95% range (± 2 SD)
• 0.009 – 0.029 g% per h
Gender Differences
Kwo et al. Gastroenterology 115;1552-57, 1998
• Different body composition.
– Less water/kg in women compared with men lower
volume of distribution in women.
• Hormonal differences
– testosterone influences ADH activity?
•
•
•
•
•
First-pass metabolism - gastric ADH?
Menstrual cycle in women?
Oral contraceptive steroids?
Liver volume ~same
Alcohol Elimination rate per kg LBM was
higher in women.
Relationship between dose of ethanol and
Cmax and AUC of the BAC profile
Blood-Ethanol, g/100 mL
0.15
0.10
(2)
0.05
(4)
0.95 g/kg
(3)
0.64 g/kg
(2)
0.80 g/kg
0.32 g/kg
0
0
60
120
180
240
300
360
420
Time From Start of Drinking, min
480
540
Blood-Ethanol Profiles
N = 48 Healthy Men
Aged 20-59 y
0.68 g/kg
Neat whisky in 20 min
Empty stomach
Blood Ethanol mg/100 mL
140
120
100
• Conditions
80
60
40
20
0
0
60
120
180
240
300
360
Time After Start of Drinking, min
Work done at Karolinska
Institute - police as subjects
420
480
–
–
–
–
–
–
Healthy men
20-59 y
Neat whisky
0.68 g/kg
Empty stomach
20 min drinking
time
– Capillary blood
samples
Blood Ethanol elimination, g/L/h
Rank ordering of blood-ethanol
elimination rates in fasting male subjects
0.20
0.20
Mean 0.126 g/L/h (N = 48)
SD 0.0173 g/L/h
95% range 0.091 - 0.16 g/L/h
0.15
0.15
0.10
0.10
0.05
0.05
0.00
0.00
10
20
30
Subject Number
40
Times needed to reach Cmax after drinking
neat whisky on empty stomach
Dose
g/kg
0.34
0.51
0.68
0.85
1.02
All
N
6
16
83
44
3
152
5-15
min
5
11
33
13
62 (41%)
35-45
min
1
3
26
24
1
55 (36%)
65-75
min
1
21
7
1
30 (20%)
95-105
min
1
3
1
5 (3%)
Note times might be different under social drinking conditions
Time to Cmax after end of drinking
Time to reach peak
BAC, Cmax
Number of subjects
(%)
0 min
4 (6%)
15 min
19 (29%)
30 min
17 (26%)
60 min
19 (29%)
90 min
3 (4%)
120 min
1 (1.4%)
N = 65 men drank 0.8 g ethanol/kg as 95% v/v alcohol
diluted with orange juice in 30 min after overnight fast.
Time to Reach Peak Concentrations under
Social Drinking Conditions
• Wright and Cameron, Alc & Alcoholism 33;495-501, 1998.
– 51 subjects drank 1 mL EtOH/kg as beer (4% v/v)
over 90 min (~2 L ) and breath analyzed 5-90 min
after end of drinking.
• Peak BrAC at mean time of 16 min (range 5-85 min).
• Ganert and Bowthorpe, Can Soc Forens Sci J. 33;137-43, 2000
– 10 subjects drank 0.37-0.52 g alcohol per kg per hour
over 3 hours. Breath was analyzed at 5-10 min
intervals for up to 7 hours after start of drinking.
• Peak BrAC at mean time of 12 min (range 4-22 min).
Zink & Reinhardt, Blutalkohol 21;422-433, 1984.
4.5
SUBJECT 2
EOD = 620 m in
Blood Ethanol, mg/g
4.0
3.5
3.0
2.5
Peak BAC
608 m in
2.0
1.5
Ingestion of 364 g ethanol (5.7 g/kg)
mainly as 4 vol% Beer
1.0
0.5
0
0
200
400
600
800
1000
Time From Start of Drinking, min
1200
Zink & Reinhardt, Blutalkohol 21;422-433, 1984.
3.5
SUBJECT 1
Blood Ethanol, mg/g
3.0
EOD = 580 m in
2.5
2.0
Peak BAC
575 m in
1.5
1.0
Ingestion of 357 g ethanol (4.7 g/kg)
mainly as 4 vol% Beer and spirits
0.5
0
0
200
400
600
800
1000
Time From Start of Drinking, min
1200
Mean Curves
Effect of
beverage
type, data
from Finland
1.8
Brandy
Beer
Blood Ethanol, g/kg
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
60
120
180
240
300
Time, min
Brandy
N = 12 men
Brandy (1.0 g EtOH per kg)
Blood Ethanol, g/kg
2.0
1.5
1.0
0.5
0.0
0
60
120
Beer
2.5
180
Time, min
240
N = 12 men
Beer (1.0 g EtOH per kg)
2.0
Blood Ethanol, g/kg
2.5
300
1.5
1.0
0.5
0.0
0
60
120
180
Time, min
240
300
Inter-individual variation and
gender differences
0.7
Blood Ethanol, g/L
Blood Ethanol, g/L
N = 22 subjects
10 men and 12 women
0.4 g/kg
0.8
ETHANOL DOSE
0.4 g/kg
0.7
0.6
MEN
WOMEN
0.5
0.4
0.3
0.2
0.1
0.0
0
60
120
180
Time after start of drinking, min
0.6
(g/kg)/0.7
0.5
0.4
0.3
0.2
0.1
0.0
240
0
60
120
180
Time, min
240
300
300
0.6
Mean Curves (N = 9)
Blood Ethanol, g/L
0.5
Plasma vs whole
blood as
specimens for
analysis
0.4
Plasma
0.3
0.2
Whole
Blood
0.1
0
0
60
120
180
240
Time, min
0.6
0.6
Male 66 kg
0.5
Blood Ethanol, g/L
Blood Ethanol, g/L
0.5
Male, 65 kg
0.4
Plasma
0.3
0.2
Whole
Blood
0.4
0.2
0.1
0.1
0
0
0
60
120
Time, min
180
240
Plasma
0.3
Whole
Blood
0
60
120
Time, min
180
240
1.4
Healthy subject, 0.8 g
ethanol per kg in 15 min
after overnight fast.
Drink
Blood Alcohol, g/L
1.2
Radial Artery
Blood
1.0
0.8
0.6
Cubital Venous
Blood
0.4
0.2
0
0
60
120
180
240
300
Time, min
360
420
480
1.0
Blood Ethanol, g/L
0.8
Male, 70 kg, 32 y
70 mL
whisky
70 mL
whisky
0.6
0.4
0.2
55 min
0.0
0
60
1.0
Blood Ethanol, g/L
0.8
120
180
240 300
Time, min
360
420
480
540
360
420
480
540
Man, 64 kg, 33 är
64 mL
whisky
0.6
64 mL
whisky
0.4
0.2
60 min
0.0
0
60
120
180
240
300
Time, min
Drnking
alcohol on an
empty
stomach in
divided doses
showing
slower
absorption of
the second
dose
Concentration-time profiles of ethanol in urine
Blood
Urine
Ethanol Conc., g/L
2.0
1.5
1.0
0.5
0.0
0
100
200
300
400
500
Time After Start of Drinking, min
600
Concentration-time profiles of ethanol in saliva
Saliva Ethanol Conc., g/L
1.6
0.54 g/kg
0.68 g/kg
0.85 g/kg
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
0
60
120
180
240
300
Time, min
360
420
480
540
Ethanol Conc. g/L
0.6
CSF
Blood
0.5
0.4
0.3
0.2
0.1
0.0
0
60
120
180
Time After Drinking, min
Ethanol Conc. g/L
0.6
CSF
Blood
0.5
0.4
0.3
0.2
0.1
0.0
0
60
120
Time After Drinking, min
180
Concentration-time
profiles of ethanol in
serial samples of lumbar
cerebrospinal fluid
ETHANOL-FOOD INTERACTION
•
•
•
•
Lowers the Peak BAC
Smaller Area Under the Curve
Diminished Feelings of Intoxication
Shorter Time to Zero BAC
•More rapid metabolism
Influence of food on ethanol parameters
Empty stomach
After food
1.5
C 0 (fast)
Widmark's rho
Dose (g/kg)/C 0
Blood Ethanol, g/L
C 0 (fed)
1.0
C t = C 0 - ßt
0.5
Time0
0
0
60
120
180
240
300
Time, min
360
420
480
540
Effect of Eating a Meal Before Drinking
Mean Curves n = 12
150
150
0.80 g/kg
Empty stomach
100
Blood Ethanol, mg/dl
Blood-ethanol mg/dl
Man 43 y, 68 kg
Ethanol dose 0.8 g/kg
Fasted
β = 13.5 mg/dl/h
After food
100
50
0
50
0
60
120
180
Time, min
Fed
β = 14.3 mg/dl/h
0
0
1
2
3
4
5
6
7
Time from start of drinking
8
9
240
300
360
Inter-individual variations
A. Drinking on empty stomach
Ethanol dose
0.3 g/kg, 10
male subjects
B. Drinking 60 min after breakfast
C. Drinking 60 min after breakfast + aspirin
0.6
0.4
0.2
0
0.4
0.2
60
120
Time, min
180
240
0.4
0.2
0
0
0
C
0.6
B
Blood Ethanol, g/L
A
Blood Ethanol, g/L
Blood Ethanol, g/L
0.6
0
60
120
Time, min
180
240
0
60
120
Time, min
180
240
Pharmacokinetics in people with GERD
Trial 1
Trial 2
Blood Ethaol, g/L
0.8
0.6
0.4
0.2
0.0
0
50
100
150
200
250
300
Time, min
0.8
Blood Ethanol, g/L
Trial 1
Trial 2
J. Forensic Science
1999;44:814-819
0.6
0.4
0.2
0.0
0
50
100
150
Time, min
200
250
300
Pharmacokinetics in women
after gastric bypass surgery
Upper gastrointestinal canal
after operation for gastric
bypass. The volume of new
stomach is ~25 mL. This
operation often leads to
mean body weight reduction
of 25-40% within 3 to 5
years.
Representative BAC Profile
GASTRIC BYPASS PATIENTS
1.2
15_F
KM F, 44 y, 74 kg, 167 cm
Blood Alcohol, g/L
1.0
0.8
0.6
0.4
0.2
0
0
60
120
180
TIme from start of drinking, min
240
Mean Curves, N = 13 subjects. Brit J. Clin.
Pharmacol Dec., 2002
Blood Alcohol, g/L
0.80
0.60
Operated
Control
0.40
30 min
0.20
0
0
60
120
180
TIme from start of drinking, min
240
Disease States and Rate of Ethanol
Disappearance from Blood
Jokipii, MD Thesis, University of Helsinki 1951
•
•
•
•
•
•
Healthy Controls (N = 42)
Dystonia (N = 17)
Hepatitis (N = 19)
Cirrhosis (N = 5)
Hyperthyreosis (N = 15)
Diabetes Mellitus (N = 21)
0.013 g/100 mL/h
0.010 g/100 mL/h
0.010 g/100 mL/h
0.010 g/100 mL/h
0.014 g/100 mL/h
0.011 g/100 mL/h
Combined results of experiments with men and
women who drank 0.50 g/kg (40% v/v) as a bolus
dose on an empty stomach
Rate of Ethanol
Elimination in Alcoholics
(induced CYP2E1 activity)
•
•
•
•
Male and female alcoholics.
BAC at start of detoxification 0.23 - 0.49 g% w/v.
6-8 specimens of venous blood taken over 24 h.
Blood-ethanol determined by headspace gas
chromatography.
• Rate of ethanol disappearance from blood
calculated as described by Widmark from the
slope of the elimination phase.
β = 0.024 g% per h
SUBJECT 2
2.5
400
2.0
300
1.5
200
1.0
100
0.5
0
0
0
5
10
15
20
25
Time From Start, h
500
3.0
Subject 7
0.5
0.4
0.3
0.2
0.1
0
β = 0.021 g% per h
0.5
0.4
0.3
0.2
0.1
0
β = 0.022 g% per h
2.5
400
2.0
300
1.5
200
1.0
100
0.5
0
0
0
5
10
15
20
25
Time From Start, h
0
3
6
9
12
15
18
21
TIME FROM START, h
24
27
EtOH-MeOH
metabolic interaction
Blood Methanol, mg/dl
0.5
0.4
0.3
0.2
0.1
0
Blood Ethanol, mg/dl
β = 0.019 g% per h
F
Blood Ethanol, mg/dl
BLOOD ALCOHOL CONCENTRATION, g% w/v
Alcoholics
Blood Methanol, mg/dl
3.0
500
0.5
0.4
0.3
0.2
0.1
0
Faster Elimination Rate in Alcoholics during Detoxification*
Subject
•
•
•
•
•
•
•
•
1
2
3
4
5
6
7
8
BAC at Start
ß-slope g% per h
0.443 g%
0.489 g%
0.398 g%
0.454 g%
0.359 g%
0.343 g%
0.337 g%
0.410 g%
0.018 g% per h
0.021 g% per h
0.028 g% per h
0.017 g% per h
0.019 g% per h
0.016 g% per h
0.017 g% per h
0.033 g% per h
Mean rate (N = 21), 0.023 g% per h (0.013-0.036)
*Alcohol & Alcoholism 27;641-647, 1992
Jones, unpublished work
Blood Alcohol, mg/dl
150
Subject Vomited and Comatose
125
100
75
50
M 110 kg
Alcohol dose 1.02 g/kg
330 ml neat whisky in 25 min
25
0
0
1
2
3
4
5
6
Time From Start of Drinking, h
7
Retrograde Extrapolation
Position of the BAC profile at the time of driving?
Was alcohol consumed after driving?
Was BAC or BrAC measured?
What allowance if any should be made for absorption
of alcohol contained in the last drink?
! Allowance for a rising BAC or BAC plateau?
! Was a urine sample taken?
!
!
!
!
! Can help to verify post-absorptive state
! What elimination rate (ß-slope) should apply?
Exact quantitative results are probably not possible
Retrograde Extrapolation
! Provided that the BAC curve was post-peak at the
time of driving and the time of drawing blood then
back extrapolation is feasible and simple.
! Ct1 = C0 - ßt1 and Ct2 = C0 - ßt2
! Ct1 = Ct2 + (ß x tdiff)
! In criminal cases best to assume a low rate of alcohol
elimination (ß-slope) such as 0.01 g% per hour.
See Stowell and Stowell, JFS, 43;14-21, 1998
Forward Prediction of BAC
! This application of Widmark’s equation has been
widely abused and has considerable uncertainty
owing to assumptions about the rate of absorption
and first-pass metabolism that might occur.
! If alcohol is taken with food then the dose of
alcohol available for absorption into the blood is
less by 10-20%.
! Drinking heavily over many hours seems to result
in larger “losses” of alcohol.
See Zink & Reinhardt , Blutalkohol 21; 422-442, 1984.
Arterial-Venous Differences in EtOH Conc.
at the Blood Sampling Compartment
Tissue of the Arm
Peripheral
vein
CA
CV
Peripheral
artery
High water content of muscle acts
as a reservoir for ethanol
Male subjects
A-V Difference g/L
0.5
0.4
A-V Difference g/L
0.4
0.3
Mean ± SD
N = 9 Subjects
0.3
0.2
0.1
0.0
-0.1
0.2
-0.2
0
60
120
0.1
180
240
300
Time
0.0
-0.1
-0.2
0
60
120
180
240
300
Time After Start of Drinking, min
360
360
Arterial-Venous Differences in
Blood Ethanol Concentration
• ABAC > VBAC during the absorption and
distribution stages during and shortly after
drinking
– mean 0.019 g% (range 0.008 to 0.043 g%).
• Occurred 10 min after end of drinking.
• ABAC = VBAC at only one time point
– 90 min (median) range 45-150 min.
– Represents equilibriation in all body water
• ABAC < VBAC at all later times
– mean -0.0029 g/L (range -0.0018 to -0.0052).
Studies in Progress
• Pharmacokinetics of ethanol in obese subjects
– People with very high BMI > 35
– What is volume of distribution of ethanol?
– What consequences for Widmark calculatiosn?
• Magnitude and time course of arterial-venous
differences in ethanol concentration.
– Implications for use of evidential breath-alcohol
analyzers.
• Comparison of glucose and amino acids on rate
of alcohol metabolism
– Both ethanol and nutrients given intravenously to
sidestep confounding influences of gastric emptying.
”Is this really necessary, your Honor?
I’m an expert.”