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

metabolie clearanee rate. These ehanges in phenylbutazone disposition in undernutrition presumably arose from reduced binding of phenylbutazone to albumin,

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

established.

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

70

Horne

die1

0-2 wks

9r

6 .-

7

6

on

:; 5

s

.S

- IN 4 r3

2

I

1

L

E.S. VESELL

P:44% P:IO% Horne C:35% C:70%

F:2 1% F:20% diel

2-4 wks 4 -6 wks 6-6 wks

Diets

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

patients, due to their dietary alterations, the ir rate of drug elimination ma y be significantly changed . Furthermore, the normal population has a certain segment involved

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

cooked while covered with foil, thereby preventing formation of polycyclic hydrocarbons on the beef, increased by lI-fold intestinal metabolism ofphenacetin in vitro

(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.

10,000

3 4 5 6 7

Hours after dose

Customory home diet

Control hospitol diet (Ist ti me)

Control hospitol diet (2nd time)

2

Chorcool- broiled beef diet

I~ -,:-_---!:----~------,:-----+-----=------: o

100 '0

c:

.2

"§

C

s

c:

8

.s 1,000

Qj

o

o

c:

.c'"Q.

o

E

.Q'"

0..

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.

(1976).

72 E. S. VESELL

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

vegetables.