While statistically significant, very small changes in plasma antipyrine half-life

(13%) and in antipyrine CI (11%) after an intensive and unusual exposure for one week

to cabbage and brussels sprouts raise .the question of how cIinically meaningful such

dietary manipulations may be. While the change in antipyrine CI produced by a diet

high in brussels sprouts and cabbage for seven days was smalI, phenacetin plasma

concentrations changed much more. For stilI other drugs, the change produced could

be even larger. Thus, more drugs, particularly commonly used drugs with low

therapeutic indices, need to be investigated before a firm answer can be given .

Finally, it must be emphasized that in patients, many simultaneously acting factors

can influence drug CI. If, in addition to dietary change, patients receive drugs with

induction potential, then these two factors - dietary change plus inducing

compounds - could markedly alter drug CI and hence the appropriate dosage of a

therapeutic agent. Such dosage changes might not be required if each factor had acted

alone in the patient without the enhancing effect of the additional factor. On the

other hand, both factors could be either nullified or further magnified by impairment

ofcardiovascular, hepatic or renal function secondary to numerous diseases.

Relationship 0/diet to temporal variation s in drug metabolism

In normal subjects rates of elimination of some drugs are prolonged after their oral

administration in the evening compared to values obtained in the morning. The

magnitude of this prolongation varies with the drug, being most extensive for drugs

whose biological half-lives are shortest. This mean diurnal variation was 30% to 40%

for aminopyrine (Poley et al., 1979), 15% for acetaminophen and phenacetin (Shively

& Vesell , 1975) but 0% for antipyrine (Vesell et al., 1977). Deprivation of sleep

failed to alter the magnitude or direction of diurnal variations in aminopyrine

TII, (Poley, Shively & Vesell, 1978). However, it was shown that diet

controlled diurnal variations in aminopyrine metabolism. These temporal

differences vanished after starvation (Figure 4). Other experiments revealed that

temporal differences in aminopyrine T'I, could be reversed in direction with reversal

ofthe feeding schedule (Shively, Simons, Passananti, Dvorchik & Vesell , 1980). In

the earlier studies on diurnal variations the normal volunteers abstained from food

for 12 h prior to the morning dose of aminopyrine. They resumed regular meals 3 h

after that dose . Thus, 3 hr before the evening dose, they ate dinner. Under this

pattern of feeding , aminopyrine T'I, was longer and aVd higher at 20.00 h than at

08.00 h. However, the direction of diurnal variation was reversed when the normal

volunteers ate 3 h before their morning dose of aminopyrine but fasted thereafter, so

that the evening dose was taken after abstention from food for 12 h. Thus, when some

other drugs with short half-lives are administered, their rates of elimination may be

GENE-ENVIRONMENT INTERACTIONS IN DRUG MET ABOLlSM 73

reduced by fasting and prolonged by food . The surprising conclusion arises that some

dietary constituents can alter the dispo sition of certain drugs. Several other

drugs ofsho rt half-l ife need to be investigated to test th is conclusion.

FED STATE • Sam

0 Spm

3

2

1

0

3

FASTED STATE

2

1

0

MP BM c BMg Df JP R$ BJ PH fK JH JO BF

Normal mols volunloor subjocls

Figure4 EtTect of starvation in 12 normal male volunteers, aged 21-24 years, on ablating

diurnal variations in the disposition of aminopyrine administered orally. Such diurnal

variations occur when normal subjectsfast for 12h before the morning dose of aminopyrine, but

have dinner 3 h beforethe eveningdose.

Theobromine as an inhibitor of its own metabo/ism and possib/y the metabolism of

other methy/xanth ines

Studies descr ibed above established etTects on drug disposition of chemicall y heterogeneous changes in diet. Work on the methylxanthine , theobromine (TB), a

chem icall y homogeneous nutrition al constituent ofsuch dietary staples as chocolate,

coffee, tea and various cola beverages, revea led that normal subjects, due to daily

dietary TB inta ke, are inhibited met abolically with respect to their capacit y to

eliminate TB (Drouillard et a/., 1978). After two weeks on a methylxanthine free diet ,

eac h ofsix healthy male subjects increased his capacity to eliminate a test dose ofTB.

Wh ile TB is not used as a drug, clo sely related methylxanthines, such as theophylline , (TP) , are .

In the same patient, during a single course of therapy, TP dos es ma y need to be

chan ged abruptly. lt was hypothesized, on the basis ofthe studies with TB described

74 E. S. VESELL

above, that dietary TB intake might influence TP dosage requirements. The

hypothesis was based on the assumption that TB intake in human subjects could

inhibit TP metabolism. This assumption was recently supported by the demonstration that in human subjects TB inhibits rates of TP elimination (Caldwell ,

Monks, Lawrie & Smith, 1979).

Effects of occupation on rates of drug elimination in normal subjects

Environmental chemicals, such as DDT, polychlorinated biphenyls (PCBs) and

polycylcic hydrocarbons, can alter, through induction, a subject's hepatic drugmetabolizing enzyme activity. Assurance of a near basal, relatively uninduced or

uninhibited state can never be complete but is partially attainable in a subject

through repeated measurements of the rate of elimination of a particular test drug,

such as antipyrine, and through a careful history of exposures at work and at horne to

compounds or conditions capable of altering near basal rates of drug elimination.

Simultaneously acting environmental factors (Figure I), each with a different

capacity in different subjects for changing rates of drug metabolism, make it

exceedingly difficult to attribute different portions of the total interindividual

variation to specific environmental factors. In this regard, a major problem in man is

that even within a single population most persons are heterogeneous with respect

both to the environmental and genetic factors known to influence drug disposition.

The task of partitioning the total interindividual variation in drug elimination of

such heterogeneous populations into component parts is further complicated because

some seemingly pure 'environmental' factors, including diets, smoking and ethanol

consumption, are closely associated with other environmental characteristics as weil

as with genetic factors .

Chronic occupational exposure to the ehernieals listed in Table 2 can alter a

patient's basal rate of drug elimination, mainly by inducing or inhibiting hepatic

mixed function oxidases that are responsible for the metabolism of many

drugs. Again choice and pursuit ofan occupation, like diet and cigarette smoking, are

complex. They represent decisions formed as a result of underlying socioeconomic,

psychological, intellectual and genetic factors. Thus, in addition to exposure at work

to chemieals listed in Table 2 that can induce or inhibit hepatic drug-metabolizing

enzymes, a given subject's rate of drug elimination may be markedly affected by

several other factors shown in Figure I.

A partial list of occupationally encountered chemieals capable of accelerating or

retarding rates ofhepatic drug metabolism appears in Table 2. This list is suggestive,

rather than complete. Completeness is impossible because of the numerous lipid

soluble organic chemieals to which subjects are chronically exposed in their

occupations that can induce their hepatic mixed function oxidases, thereby

accelerating the rates at which these subjects eliminate many drugs and other

environmental compounds.

lt would be expected that workers chronically exposed to the lipid soluble

compounds listed in Table 2 tend to have accelerated Cl of such test drugs as

antipyrine and phenylbutazone. According to this principle, workers chronically

exposed to insecticides exhibit accelerated rates of removal of these test drugs,

probably due to an inductive response of their hepatic drug-metabolizing enzymes.

By contrast, chronic exposure to lead probably inhibits these hepatic drugmetabolizing enzymes, thereby retarding, in both children and adults, CI of

antipyrine and phenylbutazone. The critical factors of daily dose and total time of

exposure influence greatly the extent to which a subject's drug-rnetabolizing enyzmes

respond to a chemical encountered at work.

Because this is a pill-oriented society, exposure to potent chemieals that can alter a

GENE-ENVIRONMENT INTERACTIONS IN DRUG MET ABOLISM 75

subject's near basal rate of drug CI is rarely limited to that subject's occupational

exposure. Such chemieals are much more commonly ingested for medicinal,

recreational or nutritional purposes than as a result only of occupational exposure.

Certain professions with continuous drug contact have higher drug intake. Thus,

complex factors in addition to exposure at work and at horne , through diet,

medication and recreation, to numerous chemieals capable of altering rates of drug

elimination can render hazardous or erroneous the attribution of a particular

subject's drug-metabolizing capacity to a simple, single compound.

A controlled experiment is necessary to assess the role of the factors listed in

Figure land the ehernieals listed in Table 2 with respect to the ir role in affecting a

subject's capacity to metabolize drugs . In th is experiment, only one factor is

manipulated independently of the others. As mentioned at the outset of this paper,

subjects in a near basal state of drug CI need to be selected for such a study. Then

each subject's CI ofa test compound is determined several time s before imposition of

this factor and again several time s after introduction of the factor. By constructing

dose-response curves, the role exerted by each factor on drug CI can be assessed

quantitatively. On the other hand, if only a single measurement of Cl ofthe test drug

is made in unselected subjects of different age, sex, ethnic background, dietary

custom, occupation, smoking habit, and medication intake, ineluding birth control

pills (Fraser, Mucklow, Bulpitt, Kahn, Mould & Dollery, 1979), no definitive

conelusion can be rcachcd concerning the role of occupation, or of any one of these

other variables, bccause these variables are all confounded. Moreover, interpretations in this study (Fraser et a/., 1979) relied solely on correlation coefficients. In

the absence of a controlled experiment, correlation coefficients prove nothing. They

may serve as initial elues on which to base subsequently the necessary type of

controlled experiment that has just been described. Further specificity in the use of a

test drug can be obtained, as mentioned earlier, by measurement of principal

metabolites in urine, both before and again after imposition ofa single environmental

change.

Experimental design is emphasized here because it may help explain the discrepant

results in Table 2 for anaesthetists. Table 2 shows that anaesthetists in one study

apparently had accelerated rates of antipyrine elimination (O'Malley, Stevenson &

Wood, 1973), whereas in another study their rates of warfarin elimination were

prolonged (Ghoneirn, Delle , Wilson & Ambre, 1975). In the former study antipyrine

was administered only once and the control group was not concurrent, whereas in the

latter study anaesthesiology residents served as their own controls with each subject's

rate of warfarin elirnination being measured on two separate occasions. The initial

measurement in each subject represented near basal rates of drug elimination before

exposure; the second measurement, taken after four months of daily exposure to the

conditions ofthe operating roorn , represented the effects of occupational exposure to

various anaesthetic gases. In addition to these critical differences between the two

studies in experimental design, other differences between them exist that also could

have influenced the results.

For these reasons, results of studies concerning effects of various ehernieals

encountered at work on the drug-metabolizing capacity of exposed workers reflect to

a large extent the experimental design of the study, They also can be greatly

influenced by multiple individual characteristics ofthe subjects investigated, as weil

as the dose of the chemical to which the subject is exposed, the route of exposure and

the duration of that exposure. These considerations again emphasize the theme of

this paper: the multiplicity of complex, dynamic interactions among genetic and

environmental factors that can determine rates of drug elimination in certain

subjects.

Table2 Occupational chemieals that alter rates ofdrug elimination depending on intensity and duration ofexposure. -I0-

Number and sex Changein test drug

ofsubjects Employedin Chemicalexposure Testdrug producedby chemical Reference

26M Insecticide plant Lindane and DDT Antipyrine Shorter plasma TIf, (Kolmodin, AzamotT &

15M Same insecticide plant, Unexposed (control) Sjoqvist, 1969)

IBM as office workers

IBM DDT plant for more DDT and 'DDT- Phenylbutazone Phenylbutazone TIf) (Poland, Smith,

than 5 years related compounds' and 6ß-hydroxycortisol Urinary excretion of Kuntzrnan, Jacobson &

excretion in urine 6ß-hydrox ycortisolt Conney, 1970)

IBM Same DDT plant, Unexposed (control)

same time

fI'

-e

14M Insecticide plant Spray ofsolution Phenylbutazone Phenylbutazone TIf) (Kolmodin-Hedrnan, 1973) rrJ V2

containing rrJ r4%lindane, t""

0.1% pyrethrum,

2.5% malathion

9M Insecticide plant Unexposed (control)

26M Tree nurseries Spray oflindane Antipyrine, Antipyrine (Kolrnod in-Hedman, 1974)

4%,2.5% malathion, Phenylbutazone Phenylbutazone

23M Tree nurseries SprayofDDT Oxazepam Oxazeparn TIf, unchanged

15M Office Unexposed (control)

IBM

3M Capacitor manufacturing Polychlorinated Antipyrine Antipyrine MCRt, (Alvares, Fischbein,

2F plant biphenyls aVd unchanged Anderson & Kappas, 1977)

3M Same plant Unexposed (control)

2F

4MC· None Chronic lead Antipyrine Antipyrine and (Alvares, Kapelner, Sassa

4FC· poisoning Phenylbutazone phenylbutazone TI! ,t,

& Kappas, 1975)

2 ?C· None Acut elead Therapy for lead

poisoning poisoning decreased these

values to ward normal

I MC· None Unexposed (control) 0

I FC· [Tl

z

[Tl

in

SM Shipyard Lead Antipyrine Antipyrine TI! ,t (Alvares, Fischbein, Sassa, Z<:

Anderson

& Kappas, 1976) ;X;

0

z

:::

10M Unspecified Lead, chronic Antipyrine Antipyrine Tv,t, MCRt; (Meredith, Campbell, [Tl

Z

these reverted to normal Moore

& Goldberg, 1976) -I

with EDT

A therapy

Z

-I

[Tl

>

23 ? Anaesthesia Operating room gases Antipyrine Antipyrine TI!) (O'Malle y et al., 1973) o-I

(volat ile anaesthetic (mea sured once) 13

agents , including ZVl

halothane , etc.)

Z

Cl

23 ? Anaesthesia Unexposed (con trol) C

0

:::

[Tl

-I

7M Anaesthesiology Undefmed volatil e Warfarin Warfarin TI! ,tmeasured (Ghoneim et al., 1975)

>

tl:l

0

residency anaesthetic agents before and after 4 months rofexposure to operating Vi :::

room

5M Anaesthesiology Unexposed (control)

residency

• Children -.J -.J

78 E.S. VESELL

References

Adithan, c., Gandhi, I. S. & Chandrasekar, S. (1978). Pharmacokinetics ofphenylbutazone in

undemutrition. Ind. J. Pharmac., 10, 301-308.

Alvares, P., Fischbe in, A., Anderson, K. E. & Kappas, A. (1977). Alterations in drug

metabolism in workers exposed to polychlo rinated biphenyls. Clin. Pharmac. Th er., 22,

140-146.

Alvares, A. P., Fischbein, A., Sassa, S., Ande rson, K. E. & Kappas, A. (1 976). Lead intoxication:

etfects on cytochrome P-450-mediated hepatic oxidations. Clin. Pharmac. Ther., 19,

183- 190.