Pharnacokinetics M and E Flashcards
Primary way that elthyl alcohol is removed and secondary
oxidative metab.
Ethyl alcohol is removed from the body primarily by oxidative metabolism
Vast majority (95%) is metabolized by the liver
Reminder excreted unchanged in breath, swear, and urine
Small amount [<0.1%] undergoes Phase II metab
Ethyl glucuronide
Ethyl sulfate
Others
What order is the metabolism of alcohol
0 order linear at midrange
Steps of conversion of ethyl alcohol
Ethyl Alcohol –alcohol dehydrogenase🡪 acetaldehyde
Acetaldehyde –aldehyde dehydrogenase🡪 acetic acid
Acetic acid –citric acid (Kerbs) cycle🡪 CO2 and water
Alcohol dehydrogenase
Oxidative process requiring NAD+
Biochem processes requiring NAD+ may be altered due to EtOH metabolism
Oxidation of fatty acids impaired – fatty liver
Gluconeogenesis [production of glucose] impaired
Cytosol of hepatocytes
Found in stomach, kidney, and lung tissues
ADH 1
Class I ADH polymorphic
Different activity
Observed differences in the rate of metabolism
Studies have demonstrated no significant difference between racial groups
Class I ADH mainly responsible for metab of EtOH
ADH 4
Expressed mainly in stomach mucosa
ADHAse catalytic activity varies
Age,gender, drinking habits,ethnicity
Reduced bioavailability of EtOH
Activity decreased after fasting
Activity decrease after alcohol abuse
Activity is lower in females
Activity inhibited by some drugs
ASA, H2-Antagonist
Zantac, Tagamet
Aldehyde Dehydrogenase
Acetaldehyde more toxic and reactive than EtOH
ALDHase: oxidation of acetaldehyde to non-toxic metabolite: acetate (acetic acid)
Untoward effects of EtOH attributed to acetaldehyde
Liver damage
Dependence
Two major isozymes
ALDH-1 and ALDH-2
ALDH 1
Higher km for acetaldehyde
Cytosol of hepatocytes but can be kidney,lung,stomach,intestine,brain,muscle, red blood cells
ALDH 2
Low km
Micochondrial enzymne
polymorphic
*2 variant inactibve present in 40-50% japanese and other asianraces
highly sennsitive to small amt. EtOH
Anabuse
Disulfiram
Blocks oxidation of acetaldehyde
5-10 x in conc
1-2 weeks post ingestion rxn
Aldehyde Flush Rxn
Symptoms
Flushing
Headache
Difficult breathing
N/V
Hypotension/tachycardia
Confusion
Other Enzyme System
Microsomal ethanol oxidizing system
Catalase
Minor pathways
Microsomal Ethanol Oxidizing Systen
Cytochrome P540 isozyme [P450 CYP 2E1]
Inducible enzyme
Rapidly lost activity [few days abstinence]
Catalase
Tertiary pathway
High conc in liver [peroxisomes]
Acts as a peroxidase, uses hydrogen peroxide [by product of various endogenous rxns] to oxidize other substances
Other minor pathway
Non-oxidative metabolites
Little interest until recently
Low conc
Difficult analyses
Ethyl glucuronide
Ethyl sulfate
Marker for EtOH consumption
Other Biomarkers Non-oxidative metabolite
Fatty acid ethyl esters
Fatty acids from breakdown of triglycerides may form esters with EtOH
Palmitate
Myristate
Stearate
Oleate
FAEE may be detected after EtOH has been eliminated
Easily hydrolyzed in vitro
Phosphatidylethanol
Rxn with phospholipids such as phosphatidylcholine
Marker for heavy drinking over several weeks
Rate of Metabolism
Moderate doses of EtOH
ADHase is saturated
Elimination or decrease in BAC follows zero-order kinetics
Applies to the elimination phase or post-absorptive phase
Elimination rates of ethanol
Most studies were performed on “normal” healthy adults
Elimination rates range from
0.01 g% per hours (10 mg%/hr) up to 0.025 g% per hour (25 mg%/hr)
TPR avg 0.02 g%/hr
Non-Linear Kinetics
Low BAC
Less than 0.02 g%
High BAC
Greater than 0.3 g%
Ethyl Alcohol Excretion
Less than 5% of alcohol dose eliminated unchanged in man
10% during periods of diuresis, profuse wearing, or hyperventilation
Excretion of alcohol can occur via expired air, urine, sweat, feces, milk, and saliva
Generally forensic interest focuses on urine
California: DUI – driver asked to void bladder and then sample is collected at least 20 minutes later
Value divided by 1.3 (assumed average urine-blood ratio) and expressed as a BAC
Blood VS Urine Alcohol
Urine generally lag behind BAC until blood value peaks
Payne et al found urine-blood ratio to range from 1.10 – 2.44, avg 1.44
Dunnet and Kimber reported a range of 0.94 – 1.40
Flanagen et al reported a range of 0.32 – 1.34
Represents an average conc over the period the urine was produced
is absorption and elimination an continuous process
As soon as alcohol is absorbed and distributed elimination begins
Bucket with a hole filling with water
