EtOH pharmacokinetics Flashcards
What is the rate of alcohol elimination in humans?
0.015% per hour,
a person with a BAC of 0.08% will take about 5–6 hours to reach 0.00%.
How is EtOH absorbed?
EtOH is highly soluble and can cross biological membranes via simple diffusion.
absorbed in the gastrointestinal tract, with approximately 20% absorbed in the stomach and 80% absorbed in the intestines71.
The rate of EtOH absorption follows first-rate kinetics72, but the presence of food can reduce the rate of absorption.
Once absorbed, the majority of EtOH enters the mesenteric vesicles, which drain into the portal vein of the liver73.
How is EtOH distributed
EtOH remaining after first-pass metabolism in the liver will be distributed into the total body fluids72.
The total body water content can vary by age, sex and weight, causing differences in the pharmacokinetics of EtOH74.
A greater blood flow to the brain and kidneys enables these organs to reach an equilibrium with plasma EtOH more quickly than tissues with less blood flow, such as skeletal muscle74.
How is EtOH metabolized?
Approximately 90% of EtOH is metabolized in the stomach and liver through first-pass metabolism72.
EtOH is metabolized in the body through two distinct pathways: the oxidative pathway and the non-oxidative pathway.
EtOH is primarily metabolized via the oxidative pathway, which converts EtOH to acetaldehyde. This reaction can be catalyzed by 3 different enzymes: alcohol dehydrogenase (ADH), CYP isoenzyme CYP2E1 or catalase63(Fig 1-3.).
Non-oxidative metabolism of EtOH is less prominent in overall EtOH metabolism, and includes the generation of fatty acid ethyl ester (FAEE) and phosphatidyl ethanol (PeTH), which are reviewed elsewhere75.
How is EtOh eliminated?
Approximately 90-95% is metabolized, and a small portion (<10%) is excreted unmetabolized via sweat, urine and exhalation83.
influenced by its rapid and relatively uniform distribution and by its elimination by
zero order kinetics, which means the elimination rate is not dependent on the concentration
EtOH elimination was first believed to be a zero-order process, meaning that EtOH is removed at a constant rate that is independent of the concentration86.
follows a Michaelis-Menten kinetics –> the rate of enzyme-catalyzed reactions will depend on EtOH concentration until the maximum velocity (Vmax) of the rate is reached, beyond this concentration, and the rate will no longer increase with EtOH concentration87.
This means that EtOH metabolism will transition from first-order kinetics (metabolism rate is proportional to EtOH concentrations) to zero-order kinetics (a constant rate of metabolism independent of the concertation), as the ADH enzymes reach saturation (Km = 1-2 mM).
What are exmaples of genetic polymorphisms for EtOH metabolism?
- ADH1B2 and ADH1B3 variants (common in some Asian and African populations) lead to faster ethanol metabolism, reducing peak BAC.
- ALDH2*2 variant leads to slow acetaldehyde clearance, causing flushing, nausea, and hangover symptoms (common in East Asians).
CYP2E1 polymorphisms affect ethanol metabolism rates and susceptibility to alcohol-induced oxidative stress.
- ALDH2*2 variant leads to slow acetaldehyde clearance, causing flushing, nausea, and hangover symptoms (common in East Asians).
What is the difference in EtOH metabolism in the fetus vs. adult?
fetal blood EtOH concentrations comparable to those of the mother83. Due to the limited expression of fetal EtOH metabolizing enzymes, the rate of elimination in the fetus is expected to be about twice as slow as in the mother94.
EtOH metabolism in the developing embryo and fetus will vary with gestational age due to the temporal patterns in gene expression.
human fetus, AHD1 activity in the liver is detected from 8 weeks into gestation but only amounts to 3-4% of adult activity, adult levels are reached around 5 years of age89.
CYP2E1 expression was detectable by week 12 in the fetal liver90and as early as week 7 in the fetal brain91.
Catalase expression was observed at week 6 in the liver92and at 27-28 weeks in the fetal brain93.
What are the differences in EtOH metabolism in the mouse vs. human?
The rate of EtOH metabolism and elimination can vary between species.
Mice metabolize drugs more rapidly than humans95, and the rate of EtOH catabolism is approximately 5 times faster in rodents than in humans96.
The lethal EtOH dose in a mouse is 8 m/kg (190 mM), which is twice as much as a human97. Hence, mice require a higher dose of EtOH to see the same effect observed in humans.
Ethanol metabolism by ADH, % of ethanol, saturation
ADh is the primary enzyme responsible for 80-90% of EtOH metabolism
dependent on EtOH concetraions – will become saturated at at low concentations Km = 1.2 mM = BAC 0.05
EtOH metbaolism by CYP2E1. Concentration? Location?
at high concentration >10 mM of EtOH the microsomal EtOH-oxidizing system of the ER is engaged which involves CYP2E1
inducible expression
this metabolism can generate a significant amount of ROS
Catalase metabolism of EtOH
can oxidize EtOH to acetaldehyde using H2O2 in peroxisomes
only minor contirbutions of about 2-5%
What is the estimated rate of EtOH elimination in humans? Mice
Although difficult to estimate due to many variables, in humans, EtOH elimination on average is 15 mg/100 mL/h, which equates to about 1 standard drink per hour77,88. C
Chronic consumption of EtOH can increase rates of elimination, due to increases in EtOH metabolic rate, one study measured the elimination rate in social drinkers (15 ± 4 mg%/h) and in alcoholics (30 ± 9 mg%/h).
Mice in mice is 550-650 mg/kg/hr
Humans is 80-90 mg/kg/hr
the rate of elimination of alcohol is 2-3 times
greater in mice than in humans (Bruckner, Anand, & Warren, 2013;
Finn, Bejanian, Jones, Syapin, & Alkana, 1989), suggesting that the
clearance rate may be a major determinant of the difference in mice
and humans that we identified in the present stud
EtOH metabolizing gene expression in the developing mouse
Like the developing human, the developing mouse has significantly lower EtOH metabolizing enzyme activities than the adult.
ADH1 activity was detectable in GD 8-9 mouse embryos98, though protein levels were about 4% of ADH1 activity in the adult mouse liver99.
By GD 17, CYP2E1 mRNA levels are detectable with qPCR, brain expression was much lower compared to other liver, lung, smooth muscle and kidney100.
Catalase activity has been reported as early as GD 898, with the level nearly doubling by GD 13101, but embryonic catalase activity levels were only 5% of that observed in the maternal liver101,102.
Describe the differences in EtoH metabolism among mouse strains
In mouse models, inter-strain differences can significantly influence EtOH metabolism.
Variations in total body water content among the strains can affect peak blood EtOH concentrations103.
Additionally, strain-specific differences in the activity of EtOH-metabolizing enzymes have been reported.
For example, the C57BL/6J strain has 1.5 times the ADH activity per gram of liver compared to the BALB/cJ strain and twice the activity observed in C3HeB/FeJ, A/J and DBA/2J strains104.
Another study reported that C57BL/6J mice have twice as much ADH activity as the congenic C57BL/6J.S strain105.
Similar inter-strain differences are noted in rat models, with Adh-1, -3, -7, and Cyp2e1 variations among Long Evans, Sprague Dawley and Fisher 344 rats106.
Examples of differences in EtOH metbaolism in different strains
Additionally, strain-specific differences in the activity of EtOH-metabolizing enzymes have been reported.
For example, the C57BL/6J strain has 1.5 times the ADH activity per gram of liver compared to the BALB/cJ strain and twice the activity observed in C3HeB/FeJ, A/J and DBA/2J strains104.
Another study reported that C57BL/6J mice have twice as much ADH activity as the congenic C57BL/6J.S strain10
