Pharmacodynamics andPharmacokinetics of Alcohol
Pharmacodynamics andPharmacokinetics of Alcohol
A.W. Jones, PhD, DScDepartment of Forensic Toxicology, University
Hospital, 581 85 Linköping, [email protected]
Presented at meeting of the California Association ofToxicologists, Santa Rosa, CA, 1-2 August, 2003.
CH3CH2OH
Pharmacokinetics Studies of the movement of drugs
into, within and out of the body
What the body does to the drug
Pharmacodynamics Studies of the effect and mechanism
of action of drugs on the body
What the drug does to the body
PharmacokineticsPharmacokinetics
The discipline known as pharmacokineticsdeals 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.
Pharmakon = drug or poison
Kinesis = movement
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
0 30 60 90 120 150 180 210 240 270 300
Time After Start of Drinking, min
0
50
100
150
Blo
od E
than
ol, m
g/dl
PeakBAC
Rise inBAC
DrinkingSpree
β-slope
Timeto
Peak
Pharmacokinetic Models
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
VC
VC
ko km
Vmax
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
DoseDose
Vmax x C-dc/dt =
km + C
-dc/dt = koCt = Co - kot
Response feature analysis of BACprofiles - noncompartmental analysis
0 100 200 300 400 500 600 700
Time After Start of Infusion, min
0
50
100
150
200
Blo
od E
than
ol, m
g/dl
Peak BAC
Co
Mino
β-slope = Co/Mino
Diffusion plunge
First-order kineticsAUC
Typical curve after intravenous Infusion
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 ofmore 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 ethanolwith focus on variability and forensic issues.
Properties of the Drug Ethyl Alcohol CH3CH2OH
Properties of the Drug Ethyl Alcohol CH3CH2OH
• 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, SpecificityPrecision, Accuracy, Specificity
• Forensic Labs* CV = 2-3%• Clinical Chemistry Labs CV = 6-9%
Within laboratory precision 0.5-1.5% CV
* Laboratories specializing in blood-ethanol assays and using standardized routines based on headspace GC and
internal standard, etc.
Between Laboratory Variation
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 ofalcohol 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
Others
N2O Xe
Ethylene
Chloroform
Cyclopropane
Halothane
Diethylether
Enflurane
Methoxyflurane
Isoflurane
Servoflurane
Mechanism of anesthesiaLipid solubility (Meyer-Overton correlation)Disruption of lipid bilayerInteraction 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.
Cl N
N OCH3
DiazepamAnxiolytic Sedative
Hypnotic
Muscle Relaxant
Anti-convulsantBenzodiazepines
Unconscious. Deep coma. Death from respiratory
depression.
0.40-0.50
Severely intoxicated loss of control of mind and body.0.20-0.30
Gross impairment of physical and mental control.0.14-0.15
Impaired balance, speech, vision, hearing, muscle
coordination. Marked euphoria.
0.08-0.09
Feelings of relaxation and warmth. Increased reaction
time. Decreased fine muscle coordination.
0.05-0.06
Mood elevation. Slight muscle relaxation.0.02-0.03
Effects of alcohol on the individualBAC [%]
BAC vs Effects close to peak concentration
0 1 2 3 4 5 6
Time After Drinking, h
0
50
100
150
200B
lood
Alc
ohol
mg/
dl
0
2
4
6
8
10
Into
xica
tion
Scor
e (s
ympt
oms)
BAC 110 mg/dL
IntoxicationScore
Alha, 1951
Alcohol Dose 1.25 g/kg(277 mL or 9.2 oz whisky/70 kg man)
Suspected drunk drivers (N = 1453) apprehended bythe police and examined by different physicians who
concluded they were not under the influence of alcohol
Percent not under influence
Number of cases
BAC, g%
0.7%100.25-0.2993.5%510.20-0.24911%1610.15-0.15925%3600.10-0.14930%4410.05-0.09930%4310.00-0.049
111-30.30-0.3497117-250.25-0.29952220-470.20-0.249517241470.15-0.199110412540.10-0.149--372390.05-0.099--263290.00-0.049
SeverlyModeratlySlightlyNoNumberBAC g%
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.
• 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
Altered synaptic activity caused by ethanol working at multiple molecular sites
* N-methyl-D-aspartate receptor
Receptors involved in some of the actions of ethanol
Effects on ligand-gated ion channels
GABA Receptor
Benzodiazepinereceptor
Barbiturate receptor
Chloride channel
GABAA inhibitory receptor EtOH potentiates the effect of GABA
Effects of Ethanol on the Brain
• 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
Alcohol is not evenly distributed in the brain.
Concentrations depend on blood flow and water
content.Tolerance
Acute ToleranceAcute Tolerance
• From studies mainly in dogs, Mellanby foundthat the degree of impairment to alcohol was greater at a given blood-alcohol concentrationon the rising portion of the blood-alcohol curve than it was at the same concentration on thedescending part of the curve.– Some toxicologists considered that the Mellanby effect
was caused by the different alcohol concentration inarterial blood reaching the brain and the venous blood returning from muscle tissue, which was assumed to be the specimen analyzed.
Widmark’s definitionsWidmark’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 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
Esophagus
Rapid absorption fromduodenum
Slow absorption across stomach wall
Pyloric sphincter
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
Slow gastric emptying
0
0.2
0.4
0.6
0.8
1
1.2
0 1 2 3 4 5 6 7 8
Time, h
Blo
od E
than
ol, g
/L
Rapid gastric
emptying
Critical Role of Stomach Emptying on Peak BACCritical 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 Distribution phase • Depends on many factors;
– Water content of the various fluids andtissues
• More H20 more alcohol.
– Importance of ratio of blood flow (F) totissue 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 WaterMeasuring 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 mgethanol per gram blood (not per mL).
1. Average rho men 0.68, rho women 0.552. Average ß men 0.15, ß women 0.16
Watson, Watson and Batt J. Stud. Alcohol 42;547-556, 1981Watson, 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 wereseeminly vital for calculation of TBW.
Anthropometric MeasurementsAnthropometric 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* 20-29 y 30-39 y 40-49 y 50-59 yp.o. Fasting 44.2 L 47.8 L 47.9 L 46.5 L (0.68 g/kg) (60.2%) (59.1%) (56.7%) (55.3%)
Anthropometric 44.4 L 45.6 L 46.5 L 45.3 L data** (60.8%) (56.5%) (55.1%) (53.9%)
Infusion of ethanol (0.6 g/kg) TBW 40.3 L (50.1%) Anthropometric data** TBW 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 incontrolled drinking experiments.
Seidel et al, Int. J. Legal Med.114;71-77, 2000
Elimination process Elimination process • Metabolism + excretion
– Metabolism - oxidation• Various enzyme systems involved
– ADH, ALDH, CYP2E1, Catalase?• Conjugation
– Ethyl glucuronide
– Excretion• Passive diffusion
– Breath, Sweat, Urine
Absorption phase
Hepatic metabolism
Excretion processes
Phase I enzymes
Phase II enzymes
Urine Breath
Organs
First pass metabolism
First-Pass MetabolismFirst-Pass Metabolism
Sampling Compartment
Liver
Oral Dose
Gut
I.V. administration sidesteps problems with first-pass metabolism
Class IV ADH Class I
ADH
First-Pass MetabolismFirst-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.
Concentration of Ethanol in Blood
The Individual
The Environment
age sex race body mass index
smoking drinking food drugs
Patho-physiology
Genetics and genomics
State of health; liver kidney gut
Activity of hepatic enzymes polymorphism
Speed of drinking Dose
Inter-individual Variations
Formate
Acetate
FormaldehydeMethanol
Alcohol-dehydrogenase
(ADH)
Aldehyde-dehydrogenase
(ALDH)
Ethanol AcetaldehydeADH1
ADH2*1, ADH2*2, ADH2*3 ADH3*1, ADH3*2
ALDH1ALDH2*1, ALDH2*2
NADHNAD+ NAD+ NADH
Alcohol and aldehyde dehydrogenase enzymes
Located in cytosol Located in mitochondria
Intra-individual Variations
Intra-individual variations
0 100 200 300
Time after bolus intake, min
0
0.2
0.4
0.6
0.8
1.0B
lood
Alc
ohol
mg/
gMale Subject 23 y
40 g ethanol in 5 minempty stomach
N = 10 experimentsDuring 9 weeks
β = 0.157 mg/g/h(range 0.14 - 0.20)
Intra-individual variations in EtOHelimination rate from blood
1 2 3 4
Alcohol Drinking Session
0.00
0.005
0.010
0.015
0.020
Elim
inat
ion
rate
β-s
lope
g/d
l/h
N = 12 male subjects consumed EtOH 0.8 g per kg body weight on 4 occasions after an overnight fast.
Mean value of ß-slope 0.0142 g%/h, range 0.0117-0.0173 g%/h
Inter- vs intra-individual variation not significantly different by ANOVA
BJCP 35;427-431, 1994
Ethanol
Acetaldehyde
Acetate coenzyme A
ADHcytosol
CYP2E1microsomes
CO2H2O
ALDHmitochondria
Excretion breath, urine,
sweat
Conjugation ethyl glucuronide
~85%
< 1% 3-5%
~10%
Toxic metabolite
Chemically reactive
CH3CH2OH
CH3CHO
CH3COOHH2OCO2
Alcohol Dehydrogenase
(ADH)
Aldehyde Dehydrogenase
(ALDH)
NAD+
H+ + NADH
NAD+
H+ + NADH
Breath Urine Sweat
Ethyl glucuronide
~5% ~0.1%
~94%
EtOH > 0.06 g%
CH3CHO
CYP2E1
Metabolic disturbances during hepaticoxidation 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 drinkingon the liver
Healthy liver removedat autopsy
Cirrhotic (orange) liverremoved at autopsy
Fatty liver, hepatitis and fibrosis are intermediate stages, although these are reversible.
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
Formate
Acetate
FormaldehydeMethanol
Alcohol-dehydrogenase
Aldehyde-dehydrogenase
Ethanol AcetaldehydeAlcohol-
dehydrogenaseAldehyde-
dehydrogenase
NADHNAD+ NAD+ NADH
Blocked by 4-methyl pyrazole
Blocked byDisulfiram
Antabuse®fomepizole (Antizol®)
Drug alcohol metabolic interactionsat 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®)
NNH
H3C
4-methyl pyrazole
Fomepizole Antizol®
N
HNH3C
CH3NHCNHCH2CH2SCH2
NCN
Cimetidine (Tagamet®)
H
N
NNH2CH2CH2
Histamine
A = Cimetidine 7 daysB = Ranitidine 7 daysC = Omeprazole 7 dayscompared with no-drug treatment, EtOH 0.8 g/kg
0 1 2 3 4 5 6
Time (h)
0
5
10
15
20
250
5
10
15
20
250
5
10
15
20
25B
lood
Eth
anol
(mm
ol l-1
)(A)
(B)
(C)
Many studies used very small doses of alcohol e.g. 0.15-0.30 g/kg and found small
increases in peak BAC 0.008-0.015 g/100 mL
Jönsson et al. Eur J Clin Pharmacol 42;209-12, 1992
Drug Drug
Drug Metabolites
Drug Metabolites
Moderate Drinker Heavy Drinker
Prolonged Therapeutic
Effect of the Drug
Diminished Therapeutic
Effect of the Drug
CYP450+ EtOH
ActivatedCYP450X
X
Acetaminophene
N-acetyl-p-benzo-quinone imine
(NAPQI)
Sulfateconjugate
~35%
Glucuronide conjugate
~60%
Glutathione conjugate
Covalent binding to tissues – cell death
CYP2E1 ~5%
Glutathione inactivation
Reactive intermediate
Hepatotoxicity
Induced by alcohol,fasting, protein deficiency
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%
53 y0.373 g%164Female
54 y0.355 g%529Male
Mean Age
Blood Alcohol
NGender
Jones and Holmgren, J. Forensic Sciences (USA), July 2003
We recently looked at all deaths in Swedenattributed to acute alcohol poisoning with alcoholas the only drug present in femoral venous blood
Deaths Ascribed to Acute Alcohol Poisoning
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.70
50
100
150
200
250
0
50
100
150
200
250Acute Alcohol
Poisoning DeathsN = 693
Mean 0.36 g/100 mLMedian 0.36 g/100 mL
Blood-Ethanol Concentration, g/100 mL
Freq
uenc
y
Normal
0.0 1.0 2.0 3.0 4.0 5.0 6.00
10
20
30
0
10
20
30
Blood-Ethanol Concentration, g/L
N = 703Mean 1.70 g/LMedian 1.50 g/LRange 0.1 to 5.6 g/L
Freq
uenc
y (%
)Deaths Ascribed to Chronic Alcoholism
Indications• Fatty Liver• Hepatitis• Cirrhosis• Pancreatitis• Cardiomyopathy• Ascites• Psychoses• Ketoacidosis
Drunk drivers in Sweden with very highblood-ethanol conc., > 0.4 g% (N = 120)*
199 g (570 mL vodka)
159 g (530 mL vodka)
0.43513 (11%)Female (65 kg)
265 g (810 mL vodka)
225 g (710 mL vodka)
0.428107 (89%)Male (75 kg)
5 h** metabolism
EtOH in body, g
Mean BAC g%
N (%)Gender (body weight)
* Swedish records (0.545, 0.544, 0.518, 0.505, g%)
** 8 g/h = 40 g = ~100 mL spirits
Physiological range of ethanolelimination rates from blood
Heavy drinkers such as drunk drivers who reach appreciably high BAC (> 0.12 g/100 mL)
0.016-0.025
Healthy people who drink moderate dose of ethanol under non-fasting conditions.
0.013-0.016
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.
0.025-0.035
Healthy people who drink moderate amounts of alcohol after an overnight fast.
0.010-0.013
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)
0.08-0.010
Conditions or treatmentBAC rate of decline g% per h
Rate of ethanol elimination in drinking drivers?
Assuming post-absorptive phase and zero order kinetics J. Forensic Sci. Vol 41, 922-926, 1996.
Time
Blo
od A
lcoh
ol C
onc. t1
t2
TimeB
lood
Alc
ohol
Con
c. t1
Example of calculating elimination rates based on double blood samples
0.0202a_2c0.21006.152b0.183
0.2170.2200.2280.248
BAC g%
2b_2c
2a_2b1b_1c1a_1c1a_1b
Pair of bloods
0.02007.352c
0.02105.552a0.02122.051c0.02021.421b0.01920.391a
BAC rate of decline g%/h
Time of day
Case (blood)
ß-Slope as a Function of Age in Male and Female DWI Suspects
Age
Blo
od-A
lcoh
ol D
ecay
Rat
e,m
g/m
l/h
<20y 20-29y 30-39y 40-49y 50-59y >60y0.00
0.05
0.10
0.15
0.20
0.25
0.30WomenMen
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.00 0.01 0.02 0.03 0.04 0.050
50
100
150
200
250
0
50
100
150
200
250
Elimination Rate, g/100 mL per h
Freq
uenc
y • Mean 0.019 g% per h
• SD 0.005 g% per h
• Median 0.019 g% per h
• Min 0.00 g% per h
• Max 0.046 g% per h
• 95% range (± 2 SD)
• 0.009 – 0.029 g% per h
Ethanol elimination rate in DWI suspectsDerived from double
blood samples
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
0 60 120 180 240 300 360 420 480 540
Time From Start of Drinking, min
0
0.05
0.10
0.15B
lood
-Eth
anol
, g/1
00 m
L
(2)
(3)(4)
(2)
0.95 g/kg
0.80 g/kg0.64 g/kg
0.32 g/kg
Blood-Ethanol Profiles
• Conditions– Healthy men– 20-59 y– Neat whisky– 0.68 g/kg– Empty stomach– 20 min drinking
time– Capillary blood
samples
0 60 120 180 240 300 360 420 4800
20
40
60
80
100
120
140 N = 48 Healthy MenAged 20-59 y
0.68 g/kg Neat whisky in 20 min
Empty stomach
Bloo
d Et
hano
l mg/
100
mL
Time After Start of Drinking, min
Work done at Karolinska Institute - police as subjects
10 20 30 400.00
0.05
0.10
0.15
0.20
0.00
0.05
0.10
0.15
0.20Mean 0.126 g/L/h (N = 48)SD 0.0173 g/L/h95% range 0.091 - 0.16 g/L/h
Bloo
d Et
hano
l elim
inat
ion,
g/L
/h
Subject Number
Rank ordering of blood-ethanol elimination rates in fasting male subjects
Rank ordering of blood-ethanol elimination rates in fasting male subjects
Times needed to reach Cmax after drinking neat whisky on empty stomach
5 (3%)30 (20%)55 (36%)62 (41%)152All111-31.02-72413440.853212633830.6811311160.51--1560.34
95-105 min
65-75 min
35-45 min
5-15 min
NDose g/kg
Note times might be different under social drinking conditions
Time to Cmax after end of drinking
N = 65 men drank 0.8 g ethanol/kg as 95% v/v alcohol diluted with orange juice in 30 min after overnight fast.
1 (1.4%)120 min3 (4%)90 min19 (29%)60 min17 (26%)30 min19 (29%)15 min4 (6%)0 min
Number of subjects (%)
Time to reach peak BAC, Cmax
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).
0 200 400 600 800 1000 1200
Time From Start of Drinking, min
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5B
lood
Eth
anol
, mg/
g
Peak BAC608 min
EOD = 620 min
Ingestion of 364 g ethanol (5.7 g/kg)mainly as 4 vol% Beer
SUBJECT 2
Zink & Reinhardt, Blutalkohol 21;422-433, 1984.
0 200 400 600 800 1000 1200
Time From Start of Drinking, min
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5B
lood
Eth
anol
, mg/
g
Peak BAC575 min
EOD = 580 min
Ingestion of 357 g ethanol (4.7 g/kg)mainly as 4 vol% Beer and spirits
SUBJECT 1
Zink & Reinhardt, Blutalkohol 21;422-433, 1984.
0 60 120 180 240 3000.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8 Brandy Beer
Bloo
d Et
hano
l, g/
kg
Time, min
Brandy Beer
Mean Curves
0 60 120 180 240 3000.0
0.5
1.0
1.5
2.0
2.5
N = 12 menBrandy (1.0 g EtOH per kg)
Blo
od E
than
ol, g
/kg
Time, min0 60 120 180 240 300
0.0
0.5
1.0
1.5
2.0
2.5
N = 12 menBeer (1.0 g EtOH per kg)
Blo
od E
than
ol, g
/kg
Time, min
Effect of beverage type, data
from Finland
0 60 120 180 240 3000.00.10.20.30.40.50.60.7 ETHANOL DOSE
0.4 g/kg
MEN WOMEN
Bloo
d Et
hano
l, g/
L
Time after start of drinking, min
0 60 120 180 240 3000.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
(g/kg)/0.7
N = 22 subjects10 men and 12 women
0.4 g/kg
Bloo
d Et
hano
l, g/
L
Time, min
Inter-individual variation and gender differences
0 60 120 180 240
Time, min
0
0.1
0.2
0.3
0.4
0.5
0.6
Blo
od E
than
ol, g
/L
Male 66 kg
Plasma
WholeBlood
0 60 120 180 240
Time, min
0
0.1
0.2
0.3
0.4
0.5
0.6
Blo
od E
than
ol, g
/L
Male, 65 kg
Plasma
WholeBlood
0 60 120 180 240
Time, min
0
0.1
0.2
0.3
0.4
0.5
0.6
Blo
od E
than
ol, g
/L
Mean Curves (N = 9)
Plasma
WholeBlood
Plasma vs whole blood as
specimens for analysis
0 60 120 180 240 300 360 420 480
Time, min
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Blo
od A
lcoh
ol, g
/LDrink
Radial ArteryBlood
Cubital VenousBlood
Healthy subject, 0.8 g ethanol per kg in 15 min
after overnight fast.
0 60 120 180 240 300 360 420 480 5400.0
0.2
0.4
0.6
0.8
1.0 Man, 64 kg, 33 är
60 min
64 mLwhisky
64 mLwhisky
Bloo
d Et
hano
l, g/
L
Time, min
0 60 120 180 240 300 360 420 480 5400.0
0.2
0.4
0.6
0.8
1.0 Male, 70 kg, 32 y
55 min
70 mLwhisky
70 mLwhisky
Bloo
d Et
hano
l, g/
L
Time, min
Drnking alcohol on an
empty stomach in
divided doses showing slower
absorption of the second
dose
0 100 200 300 400 500 6000.0
0.5
1.0
1.5
2.0 Blood Urine
Eth
anol
Con
c., g
/L
Time After Start of Drinking, min
Concentration-time profiles of ethanol in urine
0 60 120 180 240 300 360 420 480 5400.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6 0.54 g/kg 0.68 g/kg 0.85 g/kg
Sal
iva
Eth
anol
Con
c., g
/L
Time, min
Concentration-time profiles of ethanol in saliva
0 60 120 1800.0
0.1
0.2
0.3
0.4
0.5
0.6 CSF Blood
Etha
nol C
onc.
g/L
Time After Drinking, min
0 60 120 1800.0
0.1
0.2
0.3
0.4
0.5
0.6 CSF Blood
Etha
nol C
onc.
g/L
Time After Drinking, min
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
0 60 120 180 240 300 360 420 480 540
Time, min
0
0.5
1.0
1.5B
lood
Eth
anol
, g/L
After food Empty stomach
C0 (fast)
Ct = C0 - ßt
Time0
Widmark's rhoDose (g/kg)/C0C0 (fed)
Influence of food on ethanol parameters
Effect of Eating a Meal Before DrinkingEffect of Eating a Meal Before Drinking
0 1 2 3 4 5 6 7 8 9
Time from start of drinking
0
50
100
150
Blo
od-e
than
ol m
g/dl
Man 43 y, 68 kgEthanol dose 0.8 g/kg
Fasted
Fed
β = 13.5 mg/dl/h
β = 14.3 mg/dl/h
0 60 120 180 240 300 360
Time, min
0
50
100
150
Blo
od E
than
ol, m
g/dl After food
Empty stomach
0.80 g/kg
Mean Curves n = 12
0 60 120 180 240
Time, min
0
0.2
0.4
0.6
Blo
od E
than
ol, g
/L
C
0 60 120 180 240
Time, min
0
0.2
0.4
0.6
Blo
od E
than
ol, g
/LB
0 60 120 180 240
Time, min
0
0.2
0.4
0.6
Blo
od E
than
ol, g
/L
A
A. Drinking on empty stomach
B. Drinking 60 min after breakfast
C. Drinking 60 min after breakfast + aspirin
Ethanol dose0.3 g/kg, 10
male subjects
Inter-individual variationsInter-individual variations
0 50 100 150 200 250 3000.0
0.2
0.4
0.6
0.8 Trial 1 Trial 2
Bloo
d Et
haol
, g/L
Time, min
0 50 100 150 200 250 3000.0
0.2
0.4
0.6
0.8 Trial 1 Trial 2
Bloo
d Et
hano
l, g/
L
Time, min
Pharmacokinetics in people with GERD
J. Forensic Science 1999;44:814-819
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
0 60 120 180 240
TIme from start of drinking, min
0
0.2
0.4
0.6
0.8
1.0
1.2B
lood
Alc
ohol
, g/L
GASTRIC BYPASS PATIENTS
KM F, 44 y, 74 kg, 167 cm
15_F
0 60 120 180 240
TIme from start of drinking, min
0
0.20
0.40
0.60
0.80
Blo
od A
lcoh
ol, g
/L Operated Control
30 min
Mean Curves, N = 13 subjects. Brit J. Clin. Pharmacol Dec., 2002
Disease States and Rate of Ethanol Disappearance from Blood
Jokipii, MD Thesis, University of Helsinki 1951
• Healthy Controls (N = 42) 0.013 g/100 mL/h• Dystonia (N = 17) 0.010 g/100 mL/h• Hepatitis (N = 19) 0.010 g/100 mL/h• Cirrhosis (N = 5) 0.010 g/100 mL/h• Hyperthyreosis (N = 15) 0.014 g/100 mL/h• Diabetes Mellitus (N = 21) 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 theslope of the elimination phase.
0 3 6 9 12 15 18 21 24 27
TIME FROM START, h
00.10.20.30.40.5
00.10.20.30.40.5
00.10.20.30.40.5
00.10.20.30.40.5
BLO
OD
ALC
OH
OL
CO
NC
ENTR
ATI
ON
, g%
w/v
β = 0.021 g% per h
β = 0.022 g% per h
β = 0.019 g% per hF
β = 0.024 g% per h
Alcoholics
0 5 10 15 20 25
Time From Start, h
0
100
200
300
400
500
Blo
od E
than
ol, m
g/dl
0
0.5
1.0
1.5
2.0
2.5
3.0
Blo
od M
etha
nol,
mg/
dl
SUBJECT 2
0 5 10 15 20 25
Time From Start, h
0
100
200
300
400
500
Blo
od E
than
ol, m
g/dl
0
0.5
1.0
1.5
2.0
2.5
3.0
Blo
od M
etha
nol,
mg/
dl
Subject 7
EtOH-MeOH metabolic interaction
Faster Elimination Rate in Alcoholics during Detoxification*
• 1 0.443 g% 0.018 g% per h• 2 0.489 g% 0.021 g% per h• 3 0.398 g% 0.028 g% per h• 4 0.454 g% 0.017 g% per h• 5 0.359 g% 0.019 g% per h• 6 0.343 g% 0.016 g% per h• 7 0.337 g% 0.017 g% per h• 8 0.410 g% 0.033 g% per h
Subject BAC at Start ß-slope g% per h
Mean rate (N = 21), 0.023 g% per h (0.013-0.036) *Alcohol & Alcoholism 27;641-647, 1992
0 1 2 3 4 5 6 7Time From Start of Drinking, h
0
25
50
75
100
125
150B
lood
Alc
ohol
, mg/
dlSubject Vomited and Comatose
M 110 kgAlcohol dose 1.02 g/kg
330 ml neat whisky in 25 min
Jones, unpublished work
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.
Tissue of the ArmTissue of the Arm
High water content of muscle acts as a reservoir for ethanol
High water content of muscle acts as a reservoir for ethanol
Peripheral artery
Peripheral vein
CACV
Arterial-Venous Differences in EtOH Conc. at the Blood Sampling Compartment
0 60 120 180 240 300 360
Time After Start of Drinking, min
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5A-
V D
iffer
ence
g/L
0 60 120 180 240 300 360
Time
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
A-V
Diff
eren
ce g
/L Mean ± SDN = 9 Subjects
Male subjects
Arterial-Venous Differences in Blood Ethanol Concentration
Arterial-Venous Differences in Blood Ethanol Concentration
• ABAC > VBAC during the absorption and distribution stages during and shortly afterdrinking– 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 rateof 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.”