When phenacetin was administered to the seven subjects on five occasions,

intraindividual differences in the plasma half-lives ofphenacetin were more marked

than for antipyrine. The percent difference between the minimum and maximum

values for the plasma half-lives of phenacetin varied from 30% in subject C to 100%

in subjects Band D (Figure 4). The mean change in the plasma half-life ofphenacetin

from the lowest to the highest value in each individual was 63% for the seven

subjects. The mean coefficient of variation for intraindividual differences in the

plasma half-lives of phenacetin for the seven subjects was 19.5%. A substantial

portion of phenacetin is metabolized in the gastrointestinal tract and /or during its

first pass through the liver (Raaflaub & Dubach, 1975). Appreciable day-to-day

variability in the peak plasma levels of phenacetin and in the areas under the

phenacetin plasma concentration-time curves (0 ..... 7 h) was observed when this drug

was administered to the same subjects on several occasions. Large interindividual

and intraindividual differences in the areas under the phenacetin plasma

concentration-time curves in the seven subjects are shown in Figure 5. Consideration

ofall the data in Figure 5 revealed that the smallest area under the phenacetin plasma

VARIABILITY IN HUMAN DR UG MET ABOLISM 57

concentration-time curve (0 --+ 7 h) was 19 min mi-I (subject B on December 2 and

April 6) and the largest was 1110 min mi- I(subject D on April 6). When phen acetin

was adm inistered to each subject on five occasions, the percent difference between

the minimum and max imum values for the areas under the plasma concentration of

phenacetin-tirne curves varied over a 127% range in subject A and varied by 759% in

subject E. The mean change in areas under the plasma concentration of phenacetintime curves from the lowest to the highest value in each individual was 397% for the

seven subjects. The mean coefficient ofvariation for intraindividual differences in the

areas under the plasma concentration of phenacetin-t ime curves for phenacetin was

58.8% for the seven subjects. Although the plasma concentrations of phenacet in

varied dramaticall y when the dru g was administered to the same individual on

different occasions, the plasma levels of unconjugated N-acet yl-p-aminophenol

(phenacetin's major metabol ite) were similar after each administration of the drug.

Ou r data suggest marked intraindividual variability in the first pass metabolism of

phenacetin (either in the gastro intestinal tract and/or liver) as weil as intraindi vidual

differences in the plasma half-live s of phenacetin when this drug is administered

orall yon several different occasions.

10 / 21 12 / 2 1113 2124 4/6 Subjecl 10/2 1 12/ 2 1113 21 24 4/6 Subject

I I I I I I t I I I

300 A 600

100

40 0 E

10 0 B

0 200

60 0

, 60 0 200 E 10 0 F

c c E 40 0

'" 50 0

..:: 200 u G :::J 300 <l 10 00

100

600

Intraindividual variation in areas

600 0 under plasma concentration- time

--------------------- curves for phenacetin

4 0 0 Mean co e lficie nt 01 vcrio tion : 5 8 .8 %

Meon % d iffe re nce , min - mox : 397 %

20 0

Figure5 Intraindividual differences in the areas under the plasma concentration of

phenacetin-timecurves(AUC)(0 ..... 7 h)when900 mgofphenacetin was administered orallyto

seven subjects at six-week intervals on the dates indicated at the top of the Figure. For other

details, seelegend to Figure 2. Taken from data by Alvares et al.(1979)

The results of our studies indicate that unidentified environmental facto rs play an

important role in regulating human drug metabolism in normal individua ls who are

permitted to pursue anormal life-style and to eat an unrestricted diet. These studies

also indicate that environmental factors are more important in altering the

metabolism of some drugs (for example, phenacetin) than in altering the metabolism

of other drugs (for example, phen ylbut azone).

58 A. H. CONNEY eral.

Regulation of human drug metabolism by dietary factors

Since people receive most of their exposure to exogenous chemieals in the diet, it is

important to determine the effects of different components of the diet on the

metabolism and action ofdrugs and environmental carcinogens and to determine the

effects of dietary change s on the metabolism of endogenous substances such as steroid

hormones and other normal bod y substrates that are metabolized by drugmetabolizing enzymes (Conney, 1967; Conney & Kuntzman, 1971). Studies in our

laboratory indicated that increasing the ratio ofprotein to carbohydrate or fat in the

diet (Alvares et al., 1976a; Kappas et al., 1976; Anderson, Conney & Kappas, 1979),

feeding charcoal-broiled beef (pantuck et al., 1976; Conney et al.. 1976; Kappas,

Alvares, Anderson, Pantuck, Pantuck, Chang & Conney, 1978), or feeding cabbage

and brussels sprouts (Pantuck et al.. 1979)stimulated human drug metabolism. Other

studies showed that chronic ingestion oftheobromine or methylxanthine-containing

foods, such as coffee , tea and cocoa , inhibited drug metabolism (Drouillard, Vesell &

Dvorchik, 1978; Monks, Caldwell & Smith, 1979). In all ofthese studies, there was a

variation in the response ofdifferent individuals to the change in diet.

Flavanoids which are found in edible plants influence the metabolism of foreign

chemieals by human liver in vitro (Conney, Buening, Pantuck, Pantuck, Fortner,

Anderson & Kappas, 1980). The addition of flavone , tangeretin or nobeletin to

human liver microsomes activates both the hydroxylation ofbenzo[a]pyrene and the

metabolism ofaflatoxin BI to mutagens. On the other hand, the addition ofquercetin,

kaempferol, morin or chrysin to human liver microsomes inhibits the hydroxylation

ofbenzo[a]pyrene by human liver microsomes (Conney et al., 1980). Studies on the

mechanism of action of the activator flavanoids suggest that 7,8-benzoflavone and

flavone stimulate benzo[a]pyrene hydroxylation in human and rabbit liver

microsomes at least in part by enhancing the interaction between cytochrome P-450

and cytochrome P-450 reductase (Huang, Chang & Conney, 1980).

Effect of a controlled diet on intraindividual differences

in human drug metabolism

During the course of two studies on the effects of dietary factors on human drug

metabolism, ant ipyrine half-lives were determined in subjects after they were fed a

carefully controlled diet for several days, after they were fed a test diet for several

days, and after again feeding the original control diet for several days (Kappas et al.,

1978; Pantuck et al., 1979). Since antipyrine was administered on two different

occasions while the subjects received the same control diet on each occasion, we were

able to compare the intraindividual variations in antipyrine half-lives in the subjects

who were eating a controlled diet with the intraindividual variations in antipyrine

half-lives in individuals who were allowed to eat whatever they desired (Table I). The

Table 1 Effect ofa controlleddiet on intraindividual variations in antipyrinehalf-lives

Study

Uncontrolleddiet (study1)

Controlleddiet(study2)

Controlleddiet(study3)

Comparison

Study 1vs. study2

Study 1vs. study3

Study2 vs. study3

Within subject variance

4.02

0.85

0.63

F-Ratio 01variances 4.716

6.433

1.364

Degrees offreedom

28

8

10

p, Value

0.014

0.002

0.317

VARIABILITY IN HUMAN DRUG MET ABOLISM 59

In study I, antipyrine was administered on five occasions to seven subjects whose diet was not

controlled (Figure 3). In study 2, antipyrine wasadministered on two occasionsto eight subjects

receiving the same control diet for several days before each administration of the drug. A test

diet containing charcoal-broiled beefwas fedbetween the two control diet intervals (Kappas et

al.. 1978). In study 3, antipyrine wasadministered on two occasionsto ten subjectsreceivingthe

same control diet for severaldays before each administration ofthe drug. A test diet containing

cabbage and brussels sprouts was fed between the two control diet intervals (Pantuck et al.,

1979). Variance components and associated degrees of freedom were determined by

Satterthwaite's formula (Satterthwaite, 1946), and interstudy comparisons were made by the

F-test.

results of this comparison indicated that less day-to-day vanation occurred in

antipyrine half-lives when subjects were fed a constant controlled diet than when

individuals were allowed to eat whatever they desired (Table I).

Conclusions

Both interindividual and intraindividual differences occur in the biotransformation

offoreign chemieals in human beings. Large interindividual differences were found in

the rates of metabolism of benzo(a]pyrene, benzo(a]pyrene 7,8-dihydrodiol and

aflatoxin BI by sampies of human liver obtained by surgical biopsy, and similar

differences were found for the rates of in vitro and in viva metabolism of drugs.

Intraindividual differences were found in the metabolism of drugs administered to

healthy human subjects on several occasions. The amount of intraindividual

variability depends on the drug studied, and the amount of variability within a

subject can be used as an index ofthe role of environmental factors in the regulation

of human drug metabolism. Greater day-to-day variations occurred for the

metabolism ofphenacetin than for the metabolism ofphenylbutazone. Increasing the

ratio of protein to carbohydrate or fat in the diet, feeding cabbage and brussels

sprouts or feeding charcoal broiled beef for several days stimulated human drug

metabolism whereas administration of theobromine or feeding methylxanthinecontaining foods inhibited drug metabolism. Changes in the diet appear to be one

source of intraindividual variability in human drug metabolism since subjects on a

controlled diet had less day-to-day variations in rates of antipyrine metabolism than

did subjects who were eating an unrestricted diet.

Acknowledgements

We thank Mr. lohn Fu and Mr. T. Lewinson for their help with the statistical

treatment of our data and Mrs . Arlene Ott for her help in the preparation of this

manuscript. Support for these studies was derived in part from USPHS grant

ES-OI055.

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