As another example of dynamic interactions between gene and environment, let us
consider near basal rates of hepatic drug metabolism in normal subjects. Such rates,
controlled primarily by genetic factor s, are sensitive to perturbation by a large
number of environmental factors , some of which are listed in the outer circle of
Figure I. Man y ofthese factors act simultaneously and are interrelated. Accordingly,
they are joined to each other by a circle in Figure I. The se factors can exert their
effects by altering, at many different steps and sites, anormal subject's near basal,
genetically controlled rate of drug elimination. Environmental factors can change a
subject's drug respon se by altering processes of drug absorption, distribution,
metabolism, excretion, receptor action, or combinations of these. To suggest these
multiple potential sites, the arrow joining factors in the outer circle of Figure I to the
inner circle is drawn with a wavy line.
In patients additional environmental factors can alter rates of drug elimination.
Even in the same patient the relat ive roles played by each of these factors in
influencing drug dispo sition change with time and other variables, such as the course
and inten sity of the disease. Due to these multiple fluctuations, it is difficult to
identify, even at a particular time , which factors are operating and what contribution
each factor actually makes to the total drug-metabolizing capacity of a particular
patient. Therefore, the role of each factor is generally investigated in normal, non-
ENVIRONMENTAL FACTORS AFFECTING DRUG DISPOSITION
./' "<, Alcoh ol Int ake Pregnancy
............ Gastrcintes nnat'" Dietary Fact ors:
Fun ct ion I. low prote in hiOh carbohydrate
2. hiOh protein low carbohydrat.
Gastrointest inal--.........-1
Fjgure 1 This figure shows environmental factors that can alter genetically controlled rates of
drug elimination. Lines from each environmental factor are wavyto suggest that modification of
genetically controlled rates can occur at multiple levels. Such environmental efTects need not
occur directIy at the genetic level. A wavy arrow joins environmental factors to suggest that
several are associated and interdependent, rather than independent. Most ofthese factors have
been identifiedin man by the useofthe antipyrine test as describedin the text.
medicated subjects who are near basal with respect to most factors known to alter
hepatic drug-metabolizing capacity. Measurements with a test drug, such as
antipyrine, are then performed to quantify th is basal capacity in each subject; a single
en vironmental alteration is introduced, du ring which the subject' s drug-metabolizing
activity is remeasured and the change from ba sal values taken to quantitate the effect
exerted by the single environmental cha nge (Vesell & Page , 1969; Vesell , 1979a ,b,c).
with accuracy to other drugs; 2) certain environmental factors that alter the
disposition of other drugs may not always alter antipyrine pharmacokinetics.
Furthermore, results obtained in normal male volunteer subjects may not apply to
patients with a variety of disease states. These drawbacks are often outweighed by the
virtues of a carefully controlled approach using each volunteer subject as his own
contro!. Such an approach permits investigation of a single factor independent of
most others, thereby eliminating many interfering genetic and environmental
variables that confound the results obtained with the alternative experimental design
ofcomparing a control group with a different experimental group. For these reasons,
the antipyrine test has been successfully utilized to identify the impact of many
factors shown in Figure I on drug disposition.
Also for these reasons, effects of a subject's genetic constitution on that subject's
rate of drug elimination are best observed under near basal conditions where most
environmental factors in the outer circle of Figure I are carefully controlled. Under
volunteers. Reproduced from Vesell (l979c).
Percentage deviationfrom Percentage deviationfrom Percentage deviationfrom l'T1 Z
Volunteer mean antipyrine half-life mean antipyrine Cl mean antipyrine aVd -<
Day I Day 8 Day27 Day I Day8 Day27 Day I Day8 Day27 Z:::
J.Du. - 1.8 + 1.8 + 0.9 + 1.4 - 1.6 + 0.2 - LI + 0.2 + 0.7 z-l
A.G. + 4.2 -11.3 + 7.0 - 9.1 + 8.5 - 0.2 - 4.1 + 3.3 - 7.4 Z
L.W. 0.0 -12.7 +11.9 - 2.0 +12.6 -10.6 - 0.6 - 0.2 +1.2 -l l'T1
H.R. + 8.0 - 5.4 - 2.7 - 9.4 + 4.2 + 5.0 - 1.6 - 1.1 + 2.5 >'"
J.Do . - 2.7 +11.7 - 9.1 - 0.5 - 2.0 + 2.7 - 2.9 + 9.2 - 6.4 o-l
P.ß. +1.7 - 3.5 + 1.7 -1 5.6 -10.8 +21.8 - 14.5 - 9.7 +24.1 esz
R.S. + 1.0 - 1.0 + 1.0 + 3.4 + 3.2 - 6.8 + 3.0 + 2.4 - 5.4 ::: l'T1
+11.0 -16.6 +25.9 - 0.7 - 7.9 + 4.9 + 2.6 -l s.s. + 8.5 -1 8.3 >
controlled conditions, intraindividual variations (Table I), determined by measuring
at several different times the same subject's rate of elimination of an appropriate test
drug, are generally smalI, of an order of magnitude of 10% of mean values. Table I
shows that in such controlled subjects, intraindividual variations in rates of
antipyrine elimination are much smaller than interindividual variations (Vesell,
1979c). This conclusion based on the data shown in Table I confirrns previously
published work (Davies & Thorgeirsson, 1971; Kellerman , Kellerman, Horning &
Stafford, 1976; Lindgren, Collste, Norlander & Sjoqvist, 1974; Vesell , 1978).
In agreement with these observations; Alvares, Kappas, Eisernan, Anderson ,
Pantuck, Pantuck, Hsiao, Garland & Conney (1979) reported that most of five
separate measurements performed in each of seven subjects whose lifestyles were
uncontrolled yielded values for both phenylbutazone and antipyrine that deviated
from means in each subject by less than 10%. However, deviations greater than 10%
from the mean value occasionally occurred as in the last (Iifth) phenylbutazone value
exceptionally large departures from mean values suggest that at times certain
environmental factors exert an effect not present when the other determinations were
made. This interpretation is supported by the following considerations: 1)Alvares et
al. (1979) permitted an unrestricted lifestyle for their subjects, whose near basal rates
deviations from mean antipyrine values in the first three measurements for subject C
in Figure 2 from Alvares et al. (1979) can be accounted for by several characteristics
of that subject. An Oriental, with a family history of intolerance to salicylates, he
developed an adverse reaction accompanied by mild diarrhoea after antipyrine on
the first two occasions. However, on the last three occasions no adverse reactions
occurred; accordingly, antipyrine half-lives on these last three measurements were
CollectiveIy, the forementioned considerations render the antipyrine test, by virtue
of its high reproducibility in a subject under near basal, carefully controlled
conditions and its extreme sensitivity to perturbation by each of the environmental
factors depicted in Figure I, the best currently available technique to detect and
investigate gene-environment interactions capable of altering rates of drug
elimination in man. Increased specificity of the antipyrine test can be obtained by
measurement of the three main metabolites of antipyrine in urine. Such data and
their reproducibility are presented for ten unrelated normal male subjects and for
monozygotic and dizygotic twins (Penno & Vesell, in preparation).
Only four topics (genetic factors, age , diet and occupation) can be discussed, due to
limitations of space. These four topics were selected because they illustrate the
complex, dynamic interactions among genctic and environmental factors that
influence rates ofdrug elimination in normal subjects.
Effects of genetic factors on rates of drug elimination in normal subjects
Genetically controlIed differences in rates ofdrug elimination among normal subjects
under nearly basal conditions mainly involve variations in rates of hepatic drug
metabolism, rather than in rates of drug absorption, distribution, or excretion. Twin
or family studies supporting such conclusions (Vesell , 1973; LaDu, 1972; Vesell ,
1978 ; Vesell, 1979b) have been performed with antipyrine, dicoumarol, ethanol,
halothane, nortriptyline, phenylbutazone, phenytoin, and salicylate.
Several pharmacogenetic conditons provoked by a relatively small number of
drugs are controlIed by genes at a single locus (monogenic). Examples include
GENE-ENVIRONMENT INTERACTIONS IN DRUG MET ABOLISM 67
acatalasia; atypical plasma pseudocholinesterase; slow acetylation of isoniazid,
procainamide, and some sulphonamides; deficient 4-hydroxylation of debrisoquine;
deficient N-glucosidation of amylobarbitone; resistance to warfarin; glucose-6-
phosphate dehydrogenase deficiency; deficiency of methaemoglobin reductase; and
several drug-sensitive haemoglobins (haemoglobin Zurich and haemoglobin H).
Patients with these conditions can have unusual responses to certain drugs because of
reduced rates of drug metabolism (first five conditions listed above) or abnormal
interactions ofa drug or its metabolites with some receptor (last four conditions listed
above). In addition, genetic factors control large variations among individuals in the
extent of induction by some drugs of hepatic drug-metabolizing enzymes (Vesell ,
1973; LaDu, 1972; Vesell, 1979b) .
Effects of age on rates of drug elimination in normal subjects
Recent studies show that age can alter drug elimination (Richey & Bender, 1977;
Schmucker, 1978). Age serves as an example of complex, dynamic interactions that
control rates of drug elimination. To identify the manner in which drugs are handled
in apparently normal elderly subjects, the physician must examine them carefully to
exclude disease. However, changes that occur in drug disposition in the elderly are
due mainly to degenerative alterations in the heart, liver, kidney, and gastrointestinal
tract. Such changes decrease the physiological function of the affected tissue. For
example, cardiac output declines approximately one per cent each year from the age
of 19 to 86 years; a decreased proportion of the remaining blood goes to the liver,
kidney, and gastrointestinal tract. Age-induced changes in structure and function of
these organs, which are critical in determining rates ofeach pharmacokinetic process,
probably occur at different rates in different subjects. The following alterations tend
to occur in the elderly, often concomitantly, and complicate analysis of drug
disposition and response: cigarette smoking decreases or may stop; total calorific
intake declines; exercise is reduced; consumption of alcohol , tea , and coffee decrease;
and exposure to ehernieals at work and at horne decreases. Reduced calorific intake
leads to weight loss. Relations among total body fat, muscle, and extracellular fluid
change: body fat increases from 18 to 36 per cent of total body weight in men and
from 33 to 48 per cent in women as age increases from 18 to 85 years.
For any of these reasons rates of drug absorption, distribution, metabolism and
excretion can change with age. However, the magnitude of these changes varies
considerably with different drugs and different subjects; the disposition ofsome drugs
occur among older patients of the same age in the extent of the age effect , thereby
disposition change concomitantly in clderly subjects, it is often difftcult to determine
what specific factors are responsible for the pharmacokinetic characteristics of a
given drug in a particular patient. Detailed investigations of drug metabolism in
ageing subjects disclosed more complexity than initially suspected (Gillette, 1979;
Vestal, Wood, Branch, Shand & Wilkinson, 1979; Castleden & George, 1979).
Accordingly, physicians need to exercise care to avoid toxicity by individualizing the
dosage ofmany drugs administered to elderly patients.
Age-related changes in drug-metabolizing capacity may be difftcult to predict
because of multiple forms of the hepatic drug-metabolizing enzyme, cytochrome
P-450. Each form ofthis enzyme could have its own genetic control, developmental
characteristics, and drug specificity. Rates of enzyme activity, usually low in the
foetus and higher in the neonate, reach their peak in pre-adolescence. Values in
middle-age are approximately halfthose in pre-adolescence, and they decline further
steady increments throughout life would be expected. The prevalent pattern suggests
a ditTerent, more complex control in which multiple environmental conditions
interact dynamically with etTectsproduced by the genetic constitution.
Effects of diet on rates ofdrug elimination in normal subjects
Relationships between diet and drug response in human subjects were not even
suspected, mu ch less defmed, until recent carefully designed and executed studies
established a firm foothold on the subject and c1early pointed the way for future
investigations (Drouillard, Vesell & Dvorchik, 1978; Kappas, Alvares, Anderson,
Pantuck, Pantuck, Chang & Conney, 1978; Kappas, Anderson, Conney & Alvares,
1976; Pantuck, Pantuck, Garland, Min, Watterberg, Anderson, Kappas & Conney,
1979). More studies are needed with other drugs to establish relationships between
dietary factors and the individual processes of drug absorption , distribution,
excretion and receptor interaction.
Effects 0/starvation on drug disposit ion
Of all dietary manipulations, the extreme form , that ofstarvation, would be expected
to produce the most marked pharmacokinetic alteration. While in rodents fasting
greatly reduced rates ofhepatic metabolism ofsome drugs (Dixon, Shultice & Fouts,
1960; Kato & Gillette, 1965), no major changes in rates of drug metabolism occurred
in obese, otherwise healthy, human subjects after seven to ten consecutive days on a
diet in which the total daily carbohydrate intake was less than 15 g (Reidenberg &
Vesell , 1975). This diet produced ketoacidosis as weil as weight loss that ranged from
3.6 to 15 kg. When uncorrected for body weight, the apparent volume of distribution
(aVd) of both antipyrine and tolbutamide was significantly lower after fasting than
before , presumably because during fasting the early loss of body weight is mainly
from body water, rather than from fat stores or muscle mass. In each subject the
extent to which aVd decreased was proportional to the loss of body weight.
Therefore, when correction was made for body weight, fasting had no etTecton aVd of
The results disclosed that when allowance was made for body weight, neither half-life
nor c1earance ofthese five drugs was changed in obese subjects on a diet containing a
total calorific intake of less than 15 g of carbohydrate daily. While fasting decreased
sulfisoxazole excretion, this may be attributed to a decline in rate ofurine flow and a
fall in urinary pH, both favouring nonionic ditTusion of the drug back into the
circulation from the renal tubular lumen.
General conclusions regarding the failure of aeute fasting to alter rate s of hepatic
metabolism were further extended by a study of seven female patients with
confirrned, c1assical anorexia nervosa. In these patients, prolonged refusal to eat had
produced ditTering degrees of dehydration, hyponatraemia, hypochloraemia,
hypokalaemia, and anaemia (Bakke, Aanderud, Syversen, Bassoe & Myking, 1978).
Compared with age and sex matched normal nurses who served as controls, the
patients with anorexia nervosa had normal antipyrine pharmacokinetics, when these
values were correeted for body weight.
A study performed in India (Krishnaswamy & Naidu, 1977) revealed that in 15
men sutTering from nutritionaIoedema - a severe manifestation ofprotein deficiency
and resultant hypoalbuminaemia - the mean plasma antipyrine half-life of 12.8 h
GENE-ENVIRONMENT INTERACTIONS IN DRUG MET ABOLISM 69
was not significantly different from that of age and sex matehed non-smoking
eontrols (11.2 h), but higher than that of age and sex matehed smoking controls
similar to that ofsmoking eontrols (8.9 h), could be due to the fact that some ofthem
smoked cigarettes, some drank ethanol, and some were agrieultural labourers
exposed to pesticides known to induee hepatie drug-metabolizing enzymes . Thus, in
this study, severe malnutrition did not by itselfmarkedly alter antipyrine disposition,
supporting observations deseribed above for patients with anorexia nervosa and also
for obese, but otherwise normal, subjects after a seven to ten day fast. Chronic
exposure of some subjeets in this study to indueing ehernieals render the results
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