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