Wattenberg, Anderson, Kappas & Conney, 1979), have been shown to
have a significant effect on the in vivo metabolism of.drugs in humans, and these
environmental influences play an important role in causing interindividual and
intraindividual differences in human drug metabolism. Interestingly, the magnitude
of the effects of enzyme inducers or inhibitors on drug metabolism is different in
different individuals. Although most people are induced when they chronically
Page, 1969; Pantuck et al.. 1974; Conney et al.. 1976).
Both genetic and environmental factors control the rates and pathways ofchemical
variables in the absence of the other. Interindividual variations in the in vivo
metabo!ism of antipyrine, phenylbutazone, and nortriptyline are greater in fraternal
than in identical twins (Vesell & Page, 1968, 1969; Alexanderson, Evans & Sjöqvist,
1969), which suggests that genetic factors are important in the control of oxidative
drug metabolism. The importance of genetic factors in the regulation of human drug
metabolism has also been emphasized by recent studies on the oxidative metabolism
of debrisoquine (Woolhouse, Andoh, Mahgoub, Sioan, Idle & Smith, 1979), and
sparteine (Eichelbaum, Spannbrucker, Steincke & Dengier, 1979).
Intraindividual differences in the metabolism of foreign chemieals
An approach for assessing the role of environment in regulating the metabolism of a
drug is to study the metabolism ofthe drug on several occasions in normal volunteers
who are allowed to pursue a normallife style and to eat an unrestricted diet (Alvares,
Kappas, Eiseman, Anderson, Pantuck, Pantuck, Hsiao, Gariand & Conney, 1979;
Conney et al., 1979). Any change in the rate of drug metabolism that occurs in an
individual, when the drug is administered on different occasions, may be attributed to
changes in the subject's external environment and/or in physiological factors
(internal environment). It should be noted that this approach tends to underestimate
the role ofenvironment in regulating human drug metabolism since the presence ofa
potent environmental modifier of drug metabolism would remain undetected unless
the degree of exposure to the environmental substance changed during the course of
the study. In our studies, the magnitude of the effect of environment in controlling
human drug metabolism was evaluated by plasma half-life determinations after
administration ofphenylbutazone, antipyrine or phenacetin to seven normal subjects
on five occasions at six week intervals. On each occasion, the subjects were fasted
overnight, the drug was administered orally, and the plasma concentrations of the
VARIABILITY IN HUMAN DRUG METABOLlSM 55
drug were measured at various intervals after the dose. No attempt was
made to control the life styles or diets ofthe subjects during the course ofthe study.
A small amount of variability occurred in the metabolism of phenylbutazone
administered on five different occasions (Figure 2). The difference between the lowest
11 /1 12/13 1/24 3/6 4/18 Subjecl
11 / I 12113 1/24 3/6 4 /18 Subje cl
Introindividual variation in TI
Mean caefficient 01 variation : 8. 7%
Mean % dillerence. min -max : 24%
Figure 2 Intraindividual variations in plasma half-livesofphenylbutazone in normal subjects.
) was administered orally to seven subjects at six-week intervals on
maximum half-lifeof each subject wascalculated as folIows:
(max'_l) x 100.Taken from data by Alvares et al. (1979). rnm .
and highest plasma half-life for each subject ranged from 12% in subject C to 55% in
subject E. The mean change in plasma half-life ofphenylbutazone from the lowest to
the highest value in each individual was 24% for the seven subjects. The mean
Mean caef f i ci ent of vari at ion : 13.5%
Mean % differe nc e, min -max : 39%
10/7 11/18 1213 0 2/10 3/23 Subje ct
10/7 11/ 18 12/30 2110 3/23 Subject
Introindividual variation in Tl
Figure 3 Intraindividual vananons in plasma half-lives of antipyrine in normal subjects.
) was administered orally to seven subjects at six-week intervals on the
dates indicated at the top ofthe Figure. For other details see legend to Figure 2. Taken from data
coefficient of variation for intraindividual differences in the plasma half-lives of
phenylbutazone for the seven subjects was 8.7%.
Intraindividual differences in the plasma half-lives of antipyrine were somewhat
greater than for phenylbutazone (Figure 3). When antipyrine was administered to the
seven subjects on five occasions, the percent difference between the minimum and
maximum values for the plasma half-lives ranged from 20% in subject D to 74% in
subject C, and the mean change in plasma half-life of antipyrine from the lowest to
the highest value for each individual was 39% for the seven subjects. The mean
coefficient of variation for intraindividual differences in the plasma half-lives of
antipyrine for the seven subjects was 13.5%. It is of interest that subject C had
gastrointestinal side effects 8-10 h after receiving antipyrine on the Irrsttwo occasions
when he had the longest half-life for antipyrine, but no side effects were observed on
the subsequent three occasions when he had a considerably shorter half-life. Thus, in
one subject, intraindividual differences in a side effect were correlated with plasma
Introindividual voriction in TI
10/21 12/2 1/13 2 /24 4/6 Subjecl
10/21 12/2 1/13 2 /24 4 /6 Subjecl
Mean caefficient of variation '· 19.5 %
. Mean % difterence , min . -ma~ 63%
Figure4 Intraindividual variations in plasma half-lives of phenacetin in normal subjects,
Phenacetin (900mg) wasadministered orallyto sevensubjects at six-week intervals on the dates
indicatedat the top ofthe Figure. For other details, see legend to Figure 2. Taken fromdata by
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