Pharmacodynamics andPharmacokinetics of Alcohol

Pharmacodynamics andPharmacokinetics of Alcohol

A.W. Jones, PhD, DScDepartment of Forensic Toxicology, University

Hospital, 581 85 Linköping, Sweden.wayne.jones@rmv.se

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.”