Another eontribution to this topic from India (Adithan, Gandhi & Chandrasekar,
1978) measured phenylbutazone pharmacokineties in four normal male cont.rols
(mean age 30) and five undernourished, hypoalbuminaemic male subjects (mean age
36), none ofwhom smoked cigarettes or consumed ethanol chronieally. Compared to
controls, the malnourished group exhibited shorter mean plasma phenylbutazone
half-lives but inereased mean phenylbutazone apparent volume of distribution and
with a eorresponding inerease in availability of drug for metabolism and elimination.
Beeause the eonclusions could be important therapeutically, these results need to be
confirmed in studies on larger groups of undernourished subjeets. Nutritionally
deprived hypoalbuminaemic patients who reeeived drugs highly bound to albumin
may require higher doses ofthese drugs due to their enhanced rates of elimination. .
Renal elimination of eertain drugs can be altered by fasting or starvation, as
mentioned for sulfisoxazole, whose renal excretion decreased during fasting. Also,
since plasma free fatty acids (FFA) rise dramatically after 12 h of fasting (Wood,
Domenge, Bally, Renold & Thorn, 1960) and since these FFA bind albumin with an
avidity capable of displacing many highly bound drugs, fasting for 24 to 72 h would
be expected to aecelerate the rate of elimination of such highly bound drugs as
bishydroxycoumarin, diazepam, phenylbutazone, phenytoin, and warfarin. Drug
removal from the body would be hastened because displacement of drug from
albumin by FFA makes the previously bound, and henee sequestered , drug
immediately available for both metabolism and renal elimination, as in the case of
undernutrition accompanied by hypoalbuminaemia. This hypothesis remains to be
M arked a/terations in drug metabo/ism caused by shifting the proportion 01
carbohydrate to protein in an isoca/orific diet
The most dramatic change in drug metabolism caused by dietary manipulation was
deseribed by Kappas et al. (1976), who showed that on an isocalorific diet the rate of
antipyrine and theophylline metabolism was prolonged twofold as the percentage of
total calories represented by carbohydrate doubled from 35% to 70% and the
percentage of protein decreased from 44% to 10%. The percentage of total calories
represented by fat remained constant in the two diets at approximately 20%. The
pharmacokinetic values indicate that without alteration in total number of calories
the switch from high to low protein with a reverse change in carbohydrate content
affected only antipyrine and theophylline half-life and clearanee (CI), not their aVd
(Figure 2). This pattern suggests that this particular type of dietary manipulation
affected antipyrine and theophylline metabolism, rather than distribution.
Man y patients who receive drugs are debilitated and chronically ill; they may have
inadequate nutrition and also the usual proportion of their diet oecupied by
Figure 2 Theophylline half-livesin six normal subjectsmaintained on their usual hornediets
and on two test diet periods. Each bar represents mean ± s.e. mean for the six subjects. The
abbreviations are: P, protein; C, carbohydrate;and F, fat. The valuesfordiets I, 3 and 4 are not
significantly different fromeach other. The value fordiet 2 issignificantly different fromthat of
diet I(P > 0.05)and diet 3 (P > 0.01). Reproducedby permission ofKappas el al. (1976).
carbohydrate and protein may be reversed due to intravenous therapy. For such
in various diets to reduce their weight ; these individuals could also be susceptible to
the kind s of changes in drug-metabolizing capacity illustrated in Figure 2. Therefore,
drug dosage mayaiso have to be changed according to new requirements in subjects
who change their dietary patterns in ways similar to tho se shown in Figure 2.
Why does starvation cause negligible change in antipyrine metabolism , whereas on
an isocalorific diet , switching the proportion of carbohydrate to protein profoundly
alters antipyrine metabol ism? Possibly the bod y can detect the former dietary
manipulation better than the latter type. Through detection of the gross dietary
change of starvation, the bod y can compensat e by pro viding from another source, at
least for a limited time, the amino acids requ ired for protein synthesis. By contrast,
the bod y may not be able to detect, and hence compensate for, a much more subtle
switch in the proportion of the total number of calories supplied in the diet as either
carbohydrate and protein. If thi s change goes uncompensated , depl etion of protein
could reduce rates ofsynthesis of hepatic drug-rnetabol izing enzymes, which in turn
could cau se retention in the body ofsuch drugs as antipyrine and theophylline.
GENE-ENVIRONMENT INTERACTIONS IN DRUG METABOLISM 71
Effects 0/charcoal broiling on drug disposition
Not just the type of food consumed but also the method of its preparation can afTect
drug concentrations and disposition. In rats, charcoal broiled beef, compared to beef
(Pantuck, Hsiao, Kuntzman & Conney, 1975). Similarly designed studies were
performed with healthy human volunteers in whom plasma concentrations of
phenacetin (Conney, Pantuck, Hsaio, Garland, Anderson, Alvares & Kappas, 1976)
(Figure 3) and of antipyrine and theophylline (Kappas et al., 1978) were measured
both before and after a charcoal broiled beef diet. These drugs were also measured
beforeand after a course on a diet containing the same amount ofbeef, but with the
beef cooked while covered with foil. After eating charcoal broiled beef, the subjects
shortened by 22% their plasma antipyrine and theophylline half-lives (Kappas et al.,
1978). No change occurred in aYd of either drug, but Cl of both drugs increased.
Therefore, charcoal-broiling appeared to enhance hepatic oxidative metabolism of
both drugs. Figure 3 shows that phenacetin bioavailability decreased, probably due
to its accelerated gastrointestinal and hepatic uptake after charcoal broiling of beef
(Conney et al., 1976). Lack of change in the slope of the decay curve of plasma
phenacetin after charcoal broiling ofbeefimplicated a first pass efTect (Conney et al.,
1976). Since in rats the feeding of charcoal broiled beef greatly stimulated the in vitro
oxidative metabolism of both phenacetin and benzo[a]pyrene , and since the
polycyclic hydrocarbons formed on the surface ofbeefby charcoal-broiling enhance
oxidative metabolism of several drugs, it seemed logical to infer that, through
induction produced by pol ycycl ic hydrocarbons, charcoal-broiling stimulated first
pass oxidative drug metabolism in the gut.
Control hospitol diet (Ist ti me)
Control hospitol diet (2nd time)
I~ -,:-_---!:----~------,:-----+-----=------: o
Figure3 Plasma concentrations of phenacetin in nine subjects given phenacetin after eating
their customary horne diets (diet I), a control hospital diet (diet 2), a charcoal-broiled beef diet
(diet 3), and the control hospital diet for a second time (diet 4). Each subject receiveda 900 mg
dose ofphenacetin in the rnoming beforebreakfast. Reproduced by permission ofConney et al.
Stimulatory effect ofbrussels sprouts and cabbage on drug metabolism in man
In rats a diet containing certain cruciferous vegetables, such as brussels sprouts,
cabbage, turnips, broccoli, cauliflower or spinach, induced intestinal benzo[a]pyrene
hydroxylase activity, as weil as the intestinal enzymes that metabolize
7-ethoxycoumarin, hexobarbitone and phenacetin (Pantuck, Hsiao, Loub,
Wattenberg, Kuntzman & Conney, 1976; Wattenberg, 1971). Moreover, indoles
present in these cruciferous vegetables induced the gut enzymes that metabolize these
drugs. The results obtained in a study on ten healthy human volunteers showed that/
seven days on a diet rich in brussels sprouts and cabbage decreased mean antipyrine
half-lives by 13% and mean plasma phenacetin concentrations by 34% to 67%
(pantuck et al., 1979). Thus, as in rats, a diet of brussels sprouts or cabbage in man
can accelerate rates of metabolism of certain drugs , presumably due to an inductive
effect exerted on the drug-metabolizing enzymes by certain ehernieals in these
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