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The Metabolism and Pharmacokinetics of Alcohol in Man

Article  in  Journal of the Forensic Science Society · February 1977

DOI: 10.1016/S0015-7368(77)71115-6 · Source: PubMed

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3.Forens. Sci. Sac. (1977), 17, 49

The Metabolism and Pharmacokinetics of Alcohol

in Man
P. W. MULLEN
The Department of Pharmacology, Materia Medica and Therapeutics,
The University of Manchester, Manchester, England, M I 3 9PT.

Recent advances in the metabolism and pharmacokinetics of alcohol are reviewed.

The metabolism of alcohol by cellular dehydrogenases leads to an increased NADHINAD
cofactor ratio, which in turn alters normal biochemical processes. The elimination of
alcohol from the body is best described in terms of Michaelis-Menten rather than zero-
order kinetics. The Michaelis-Menten parameters ,,'/ and K , in the "typical" 70kg
man appear to be approximately 25~0mg/(100ml~ hr) and IO~5mg/100ml,respectively.
The merits of pharmacokinetic principles in forensic toxicology are discussed brigy.

Introduction
Research over the past two decades has led to the accumulation of much
new information regarding the biochemistry and pharmacology of ethanol.
The present paper is restricted to an outline of our present understanding of
the metabolism and in viva elimination kinetics of this, society's most widely
used and abused drug. Due to the possible forensic implications, emphasis will
be placed on recent findings concerning the pharmacokinetics of alcohol in
man.

Metabolism
*
Ethanol is eliminated from the body principally by metabolism in the liver
(approximately go%), with minute amourits being excreted unchanged in the
breath, urine and other body fluids (Clark et al., 1941; Hawkins and Kalant,
1972). I t has long been known that alcohol may be utilized by the body for
its caloric value (7-1 Calories/gram) (Atwater and Benedict, 1896) through
its total oxidative metabolism (Figure 1) to carbon dioxide and water via
acetate (Leloir and Mufioz, 1938; Hawkins and Kalant, 1972). Apparently
this "alcohol as food" concept deceptively contributed, a t least in part, to the
view held until recently, that the toxic manifestations associated with chronic
alcohol abuse (e.g., hepatitis, fatty liver and cirrhosis) resulted not from alcohol
per se, but from an inadequate dietary supply of essential substances (especially
certain B vitamins) concurrent with a high, alcohol derived caloric intake
(Lieber, 1973; Lieber, 1976). I t now appears however, that alcohol itself, or
perhaps a metabolite intermediate, is responsible for many of the pathological
changes observed in the livers and other organs of chronic alcoholics (Lieber,
1973). Many of the adverse effects of alcohol seem to be linked to its bio-
transformation although dietary deficiencies associated with long-term alcohol
abuse may well be important in exacerbating the basic pathological chemistry
(Lieber, 1973; Majchrowicz, 1975). As seen below, the undesirable toxic
effects of long-term alcohol use may be partially explainable in terms of an
altered intracellular redox state (Forsander, 1966; Rawat, 1968; Lieber, 1973).
Within the hepatocyte the oxidative metabolism of alcohol to acetate via
acetaldehyde is effected by the enzymes alcohol dehydrogenase (ADH) and
aldehyde dehydrogenase (AldDH) (Figure l ) , the former being the site of the
rate limiting step (Hawkins and Kalant, 1972). I n this pathway the con-
comitant formation of the reduced cofactor NADH is of central importance in
49
 Ethanol n -Acetic
Acetaldehyde acid

NAD NADH NAD NADH

$.
Acetyl CoA.

j (Enters
j KrebS Cycle)
I

i
C 0 2+ H 2 0

Figure 1. An outline of the hepatic metabolism of alcohol. Most alcohol in the body is meta-
bolized to acetate by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AldDH)
located in the cytoplasm and mitochondria respectively. Both enzymes utilize the cofactor
nicotinamide adenine dinucleotide (NAD). At higher concentrations some alcohol may be
metabolized by a microsomal ethanol oxidizing system (MEOS) requiring reduced NAD
phosphate and molecular oxygen.

understanding the biochemical mechanisms underlying alcohol's adverse

effects. I n fact, 'it is the altered redox state caused by a n increased NADHINAD
ratio which is thought to be responsible for the numerous biochemical changes
associated with both acute and chronic alcohol use (Forsander, 1966; Rawat,
1968; Lieber, 1973). Animal *dies have shown that the administration of'
ethanol, by increasing the relative levels of NADH, increases the liver con-
centrations of: lactate (pyruvate), a-glycerophosphate (dihydroxyacetone-
phosphate), P-hydroxybutrate (acetoacetate), malate (oxaloacetate), glutamate
(a-ketoglutarate) and possibly other endogenous substances, the metabolism of
which are mediated by enzymes dependent upon the NADHINAD couple
(Forsander, 1966; Rawat, 1968; Lieber, 1973). (The compounds in parentheses
represent the other "half" of the substrateIproduct pair, which are of course
relatively decreased by the increased ratio of reduced to oxidized cofactor.)
Without going into detail (see Lieber, 1973 and 1976), the net effects of such
altered biochemistry could include: (i) impaired gluconeogenesis (alcohol
induced hypoglycaemia is a recognized clinical phenomenon), (ii) hyperuri-
caemia (attacks of gout have long been blamed on the overindulgence of
alcohol-the increased serum lactate competes with uric acid for renal excre-
tion) and (iii) fatty infiltration of the liver (dietary and endogenous fatty acids
tend to accumulate with chronic alcohol use, since their oxidation via the
Kreb's cycle is competitively decreased and, in addition, the increased
a-glycerophosphate/dihydroxyacetone phosphate ratio favours the formation
of triglycerides) .
I n addition to the biotransformation pathway outlined above, a small
quantity of ethanol may be oxidized to acetate by two other enzyme systems-
the microsomal ethanol oxidizing system (ILIEOS) (Figure 1) (Lieber and
De Carli, 1970; Lieber, 1973) and a peroxide dependent catalase (Keilin and
Hartree, 1945). The relative importance of these minor metabolic routes is
far from established and arguments for and against their involvement in alcohol
metabolism will not be detailed here. Suffice it to say that there is considerable
evidence to suggest that a t higher alcohol levels a microsomal enzyme system
dependent upon NADPH (Figure 1) does contribute to the overall breakdown
of this substance (Lieber and De Carli, 1970; Lieber, 1973). Indirect support
for the MEOS derives from findings with experimental animals showing that
alcohol pretreatment causes a visible proliferation of hepatic smooth endo-
plasmic reticulum together with increased levels of cytochrome P,,, and
enhanced metabolism of certain drugs, indicating induction of drug meta-
bolizing (microsomal) enzymes (Lieber and De Carli, 1970; Lieber, 1973;
Lieber, 1976).
Finally, concerning both the metabolic and toxic aspects of alcohol in man,
it is of interest that blood acetaldehyde levels are reportedly greater in alco-
holics than in normal individuals given the same dose of alcohol (Korsten
et al., 1975). It has been suggested that the higher acetaldehyde levels in
alcoholics may be due to an adaptive increase (induction) in the MEOS and
that the toxicity of prolonged alcohol use may in fact be caused by this inter-
mediate (Korsten et al., 1975). Similarly the observed occurrence of methanol
in the blood after alcohol ingestion has led to the hypothesis that this product
may also be responsible for certain adverse effects (particularly on the central
nervous system) related to human alcohol use (Majchrowicz, 1975).
Pharmacokinetics
For clinical and forensic purposes it is generally assumed that the elimination
of alcohol from the body occurs at a constant rate, even though this assumption
is based on work extending back to that of Widmark (1933) nearly 45 years ago.
Widmark's (1933) P factor, used to describe the decrease in blood alcohol
concentration per unit time (usually mg/(lOOmlxhr)=P,,), is based on
findings suggesting that the rate of alcohol disappearance from the blood is
independent of the concentration. (An arithmetic plot of concentration against
time appears to be linear over a range of measured blood alcohol values). In
other words, the Widmark (3 factor assumes that alcohol elimination is a
zero-order process in contrast to the apparent jirst-order pharmacokinetics
observed for most drugs.
Simply stated however, recent investigations reveal that alcohol elimination
may be thought of as lying somewhere between the limits of zero- and first-order
kinetics. Actually, it has been known for some time that at low blood alcohol
concentrations (say, < 15mg/100ml) the concentration-time curve tends to
become nonlinear (Lundquist and Wolthers, 1958) and that a slight change in
elimination rate (slope) occurs in response to a change in dose or peak con-
centration (Eggleton, 1940; Newman, Wilson and Newman, 1952). More
recently, Wagner and co-workers have provided considerable evidence that
the elimination of alcohol in man may be appropriately described by the
(enzyme) kinetic concepts of Michaelis and Menten (1913) as initially employed
by Lundquist and Wolthers (1958) (Wagner and Patel, 1972; Wagner, 1973;
Wagner et al., 1976; Wilkinson et al., 1976).
The Michaelis-Menten equation
dCa
- - - -
Vmax . Ca (1)
dt Km + Ca
in this context indicates that the rate of decline in blood alcohol concentration,
Ca with time, t is nonlinear and dependent upon the Michaelis-Menten
constants, VmaX(the theoretical asymptotic maximal decay rate), and K m (the
alcohol concentration at Vmax/2).
As mentioned previously most drugs obey first-order elimination kinetics-
the change in concentration, C D with time, t being exponential with the rate
at any given instant dependent upon the prevailing concentration according
to equation (2) :
where k, is the characteristic first-order elimination rate constant expressed in
units of reciprocal time (usually h-1) . After a single dose k, is readily determined
,,
from a logarithm of the concentration versus time plot ( a "semi-log plot7')-
it is equal to the slope multiplied by 2.303 (Gibaldi and Perrier, 1975).
I n contrast, in a true zero-order process such as that underlying the Widmark
(1933) assumptions, the rate of decrease in concentration, C D is constant such
that the following relationship would apply:
dC D (3)
-- = - k,
dt
where k,, the zero-order rate constant, is merely the slope of a simple arithmetic
concentration-time plot.
Examination of equation (1) reveals that the Michaelis-Menten relationship
can be reduced to approximate either a first- or zero-order process depending
on the (alcohol) concentration. Thus, at low concentration relative to K m
(ie., Ca < c K,) equation (1) will reduce to :
dCa Vmax (4)
- - --
dt Km
. Ca
which is analogous to the first-order rate equation (2) while a t high concen-
trations (Ca > > K m ) equation (1) will assume the zero-order type of
relationship ;
dCa (5)
-- = -Vmax
dt
A typical plot of blood alcohol concentration versus time data would appear
similar to the hypothetical curve shown in Figure 2, which illustrates a pseudo-
linear phase tailing off to a nonlinear (exponential) phase at low concentrations.
The slope of the pseudolinear phase however, tends to vary with the dose of
alcohol ingested. Thus, using data (mean of results obtained with 8 volunteers
each given 4 different oral doses of alcohol) from a recent paper (Wagner et al.,
1976) it can be seen in Figure 3 that the rate of decrease in blood alcohol level

Time

Figure 2. A hypothetical blood alcohol concentration versus time curve. An apparently linear
decay is followed by an exponential phase at low concentrations.
(i.e., slope in mg/(lOOmlxhr) of the pseudolinear phase =$) increases non-
linearly with the amount of alcohol consumed.
Due to their nonlinearity the 4 data points in Figure 3 were found to fit the
Michaelis-Menten type of relationship expressed in equation (6) :

where p is the rate of change in concentration and D is the alcohol dose. The
terms P,, (the theoretical maximal value of P) and Kd (the dose at Pmax/2)
are analogous to Vmax and K, in equation (1) respectively. To obtain the
curve through the points in Figure 3 P and Kd were estimated by the follow-
ing linear transformation (Hofstee, 1952) of equation (6) :

(This linear transformation has been shown (Dowd and Riggs, 1965) to provide
more reliable estimates of Michaelis-Menten constants (Pmax and Kd in this
case) than the double reciprocal plot of Lineweaver and Burk (1934) employed
by Wagner et al., (1976) in their assessment of the relationship between slope
and peak concentration). A least squares linear regression of P versus P/D
provided Kd and pmax values of 21.3g and 22.2mg/(lOOml x hr), respectively.
O n the basis of results reported in three papers (Lundquist and Wolthers,
1958; Wagner et al., 1976; Wilkinson et al., 1976) one can assume that for
alcohol elimination in man, the Michaelis-Menten parameter in equation (1)
would have the following approximate (mean) values:
K, = 10.5 mg/100ml
Vmax = 25~0mg/(lOOmlx hr)

Figure 3. The relationship between the apparently linear slope of elimination (8) and the
dose (D) of alcohol administered (data taken from Wagner et al., 1976). Each point represents
the mean obtained in 8 volunteer subjects. Doses (15, 30, 45 and 60ml of 95% alcohol) have
been converted to grams assuming that 95% alcohol contains 75.41g absolute alcohol per 100ml.
The line through the 4 points was constructed using the following equation:
8= - Pmax.
-- D
K, + D
with PmaXand Kd values of 22.2mg/(lOOmlxhr) and 21.3g, respectively (see text).
 In this context, K, is an in vivo pharmacokinetic parameter, its value being
a composite dependent upon many dispasitional and metabolic factors.
Interestingly, however, its magnitude is remarkably similar to the K, value
reported (Blair and Vallee, 1966) for human liver ADH in vitro (approximately
1-0mM = 4.6mg/ 100ml).
Since alcohol is distributed in total body water (approximately 0*601/kg)
this Vmax value corresponds to a theoretical maximal elimination rate of
10.5g of alcohol per hour for the average 70kg man.
Observations relating the rate of change in blood alcohol with the dose
administered (or peak concentration attained) are consistent with the assump-
tions of Michaelis-Menten, but not zero-order, kinetics and therefore the
reduction of equation (1) to the form of equation (4) is not warranted except
perhaps at exceptionally high (lethal?) alcohol levels (Wagner et al., 1976).
Support for Wagner's conclusions has recently been provided by Dubowski
(1976) who also found a n increase in elimination rate(s1ope =mg/( 100ml x hr)
with an increase in dose or blood alcohol level. The need for caution in assuming
zero-order alcohol elimination kinetics is emphasized by a report in which a
female patient survived a measured blood alcohol concentration of 780mg/
lOOml which appeared to decrease exponentially over a n 11 hour period to
1901ng/100ml (Hammond, Rumack and Rodgerson, 1973).
Although the present work is not intended to be a n exhaustive review of the
literature, developments in two recent and novel aspects of alcohol pharma-
cokinetics merit brief mention: the "pharmacokinetic interactions" between
alcohol and other drugs (Wagner, Weidler and Lin, 1976) and the "chrono-
pharmacokinetics" of alcohol (Sturtevant et al., 1976). with regard to the
former, it is well recognized that alcohol and certain barbiturates in combina-
tion appear to be synergistically toxic, partly as a result it seems, of competi-
tively inhibited barbiturate metabolism (Coldwell, Paul and Thomas, 1973),
(further evidence for the involvement of the MEOS?). Now, Wagner, Weidler
and Lin (1976) have found that in the cat, administration (iv) of the P-
adrenergic antagonist propranolol elicits a dramatic decrease (26%) in
equilibrium blood alcohol concentrations. The mechanism underlying this
observation is unknown, but it is possibly related to diminished blood flow to
the liver. The term "chronopharmacokinetics" was coined to delineate the
study of possible circadian influences in pharmacokinetics. I n a recent paper
Sturtevant et al. (1976) have suggested that the zero-order rate of alcohol
elimination in man varies according to a n apparent time dependent biorhyth-
micity. However, in view of the dose-dependent elimination rate discussed
above, much more experimentation needs to be carried out in order to establish
a n unequivocally significant circadian element in alcohol elimination (rather
than in, for instance, absorption) kinetics.

Concluding - Comments
This paper represents a n attempt to review and update our knowledge
of the metabolism and pharmacokinetics of alcohol in man. An awareness of
recent developments in these areas (particularly pharmacokinetics) should
stand the forensic scientist in good stead. Although the Michaelis-Menten
approach to understanding alcohol elimination may appear to be "merely
academic" to the pragmatic bench toxicologist, he should realize nevertheless,
that thc concept of a constant rate of decrease in blood alcohol levels is not
inviolable. I n legal cases where retrospective estimates of blood alcohol con-
centrations are required, the forensic expert must be knowledgeable of the
hazards inherent in such extrapolative procedures in light of new pharma-
cokinetic information.
Back extrapolative determinations of blood alcohol levels based on a single
known concentration (particularly if low-less than the K, value) must often
yield estimates bordering on wild guesses. As a n ideal minimal requisite,
educated guesses or better would require several data points for the derivation
of the Michaelis-Menten parameters, K, and Vmax, characteristic of the
individual in question. Admittedly, such data are seldom available to the
forensic scientist. Nevertheless, with the continuing advance in highly sensitive
analytical techniques, one should not totally dismiss the possibility of future
investigations in "forensic pharmacokinetics".
Acknowledgement
The author is indebted to the invaluable technical assistance of Mrs Claire
Hornby, BSc.
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