The Malnourished Child, edited by Robert

M. Suskind and Leslie Lewinter-Suskind.

Nestle Nutrition Workshop Series, Vol. 19.
Nestec Ltd., Vevey/Raven Press, Ltd.,
New York © 1990.

Drug Metabolism in
the Malnourished Child
Sarqj Mehta

Department of Gastroenterology, Postgraduate Institute of Medical Education and

Research, Chandigarh 160012, India

In the human environment, there are numerous chemicals and drags that gain en-
try to the body through ingestion, inhalation, and absorption through the skin, eyes,
and orifices. The entry or absorption of a drag is immediately followed by its distri-
bution in blood, body fluids, and tissues. Drags are mostly lipid-soluble, weak or-
ganic acids or bases of low molecular weight. These properties facilitate the process
of absorption. In the blood, part of the drag is bound to plasma proteins, and part
remains free. Bound drag is available neither for action in the tissues nor for bio-
transformation or excretion. The process of biotransformation generally converts
drags into compounds that are polar and in a more ionized state at physiologic pH,
more soluble, less bound to proteins, and less able to penetrate cell membranes. In
this form, drags can be eliminated from the body with ease. The major organ in-
volved in this process is the liver.
Protein-energy malnutrition (PEM) is widespread in the less privileged communi-
ties of the world. It particularly afflicts infants and children, because of the demands
of growth and development on nutritional resources. Children are also more vulner-
able to infection as a result of overcrowding, poor hygiene, and decreased host im-
munity. They are thus in greater need of medication than many other sections of the
population. However, PEM imposes biological alterations on various organs includ-
ing the liver, which affect their handling of drags. In spite of this, drags continue to
be given to malnourished children in conventional doses calculated on the basis of
age or body weight, and these may be inappropriately large. Little attention has
been paid to this subject, so this chapter will focus on the intimate relationship that
exists between nutritional status and drag metabolism in children and will indicate
the need to determine drag dosage scientifically in the malnourished child.

BIOPROCESSES OF DRUG DISPOSITION

It is important to understand the major steps of drag disposition, which can con-
veniently be classified into four bioprocesses: absorption, distribution, biotransfor-
mation, and elimination.
329
330 DRUG METABOLISM IN MALNUTRITION

Absorption of drugs is primarily dependent on their physicochemical properties.

Lipid solubility, low molecular weight, and state of non-ionization enhance their
passage through biological membranes. Absorption of drugs occurs mostly by the
process of passive diffusion, though active transport utilizing energy or pinocytosis
is required for certain drugs. The majority of drugs are administered by the oral
route. Absorption by this route is not necessarily complete. The rate of absorption
varies with local conditions, such as the emptying time of the stomach, pH of the
environment, and the state of the intestinal mucosa. The net absorption and rate of
absorption can be determined by appropriate pharmacokinetic studies (1).
The distribution of drugs in the various body fluids, e.g., intravascular, extracel-
lular, and intracellular fluids and body cavities, is dependent on their specific physi-
cochemical characteristics. It is dependent on (a) the relative rate of blood flow to
the organ and (b) the binding affinity to tissue and plasma proteins. Based on the
distribution characteristics of a drug, a suitable pharmacokinetic model needs to be
selected for its study, that is, one-compartment, two- or three-compartment, or mul-
ticompartment model.
Biotransformation is the bioprocess whereby lipid-soluble chemicals, which are
weak organic acids or bases, are converted into more water-soluble, polar com-
pounds, capable of being ionized at physiologic pH, less bound to plasma and tissue
proteins, and less able to penetrate cell membranes. After undergoing this chemical
alteration, drugs are ready for elimination (2,3). Most drugs are also inactivated
during this process.
Biotransformation is controlled by tissue enzymes, which are present mostly in
the hepatic microsomes. The kidney, lungs, and gastrointestinal tissue participate in
the process for some drugs. Preparatory reactions (phase I) include the simple chem-
ical reactions of oxidation, reduction, and hydrolysis (2); more complex phase II re-
actions are synthetic, involving conjugation of drugs to endogenous substrates such
as carbohydrates, amino acids, or inorganic sulfates (2,3).
Microsomal enzymes are located in the endoplasmic reticulum (ER). Microsomes
with intact molecular and functional properties can be obtained by centrifugation
and provide an important tool for investigation of the process of biotransformation
(3).
Elimination occurs chiefly through the kidney. Other organs that may take part
are the skin, lungs, the biliary system, and the gastrointestinal tract. The processes
involved in elimination by the kidney include (a) glomerular filtration, (b) active tu-
bular secretion, and (c) passive tubular secretion. Unmetabolized drugs are filtered
by the glomeruli. Part of the filtrate is reabsorbed by the tubules. Depending on their
physicochemical properties, varying amounts of drugs are eliminated into the urine
by glomerular filtration. Active tubular secretion may occur for some drugs that are
not filtered by the glomeruli (3). Passive tubular excretion occurs for most of the
water-soluble highly polar and ionized compounds or metabolites.
The rate of elimination of a drug from the body is dependent on its biotransforma-
tion and subsequently on the process of tubular excretion. Pharmacokinetically, this
can be calculated from the slope of the elimination curve of timed plasma concentra-
tions after administration of a single dose of the drug (4).
 DRUG METABOLISM IN MALNUTRITION 331

PATHOPHYSIOLOGY OF PEM IN RELATION TO DRUG DISPOSITION

PEM affects almost every organ in the body including those involved in drug dis-
position. The gastrointestinal tract is affected almost in its entire length. Stomach di-
latation, mucosal atrophy and hypochlorhydria (5,6), villous atrophy and infiltration
of the lamina propria of small bowel, and malabsorption of nutrients (7,8) are well-
documented. Hypoalbuminemia occurs as a result of reduced synthesis of albumin.
There is an increase in total body water, with a marked increase in extracellular
water (9). Cardiac output decreases, as do renal blood flow and glomerular filtration
rate (10,11).
The liver is very sensitive to dietary protein and energy deficiencies. The charac-
teristic fatty infiltration of hepatocytes extending from the periportal areas has been
observed under light microscopy. Electron microscopy demonstrates the effects on
several organelles including mitochondria, endoplasmic reticulum (ER), and ribo-
somal proteins (12,13). A decrease in phospholipids affects the structural lipids of
cell membranes (14). The ER is the site of many drug-metabolizing enzymes. The
structural alterations in the ER are likely to be accompanied by functional changes
as well.
The most frequently used animal model to study the effects of PEM on drug me-
tabolism is the protein-deficient rat. The information obtained has been reviewed by
Campbell and Hayes (15) for drugs, and by Drill (16) for toxins. The increased tox-
icity of carbon tetrachloride, heptachlor, and octamethyl-pyrophosphate (17,18) and
the prolonged sleeping time induced by hexobarbital (19) in protein-deficient rats
suggest a decreased capacity of the liver to oxidize these substances. Subsequent
work gave support to these observations and demonstrated a decrease in cytochrome
P-450 and in flavoprotein reductase, n-methylase, and analine hydroxylase activities
in protein-deficient rats (20,21). Rumack et al. (22) observed a decrease in the activ-
ity of mixed function oxidase, protein phospholipid, flavoprotein reductase, and cy-
tochrome P-450 in the protein-deficient rhesus monkey. In another study on young
rhesus monkeys with protein-energy deficiency, the half-life of antipyrine was
found to be increased and its clearance significantly decreased (23). Decreased ac-
tivity of aminopyrine-JV-demethylase in the hepatic tissue of malnourished animals
was found simultaneously.
Information regarding phase II or conjugating drug enzymes is limited. Studies in
protein-deprived rats demonstrated an enhanced capacity to conjugate nitrophenol
and aminophenol to glucuronic acid (21,22). Conjugation to sulfuric acid was not
affected. In sharp contrast, Smith et al. (24) found a decrease in conjugation of
chloramphenicol to glucuronic acid in protein-deficient guinea pigs. In the young
rhesus monkey subjected to chronic protein and energy deprivation, the plasma half-
life of chloramphenicol was found to be increased and its clearance decreased. Si-
multaneously, there was a decrease in specific activity of chloramphenicol specific-
uridine diphosphate (UDP) glucuronyl transferase in the hepatic tissue (25).
Despite the excellent and carefully conducted animal experiments, extrapolation
to the human is difficult as a result of species differences, difficulty in simulating
human malnutrition, and uncertainties about the inferences to be drawn regarding
332 DRUG METABOLISM IN MALNUTRITION

drug disposition in the organs and tissues. Direct measurements in humans, there-
fore, are still required. Such information has been obtained for some drugs em-
ploying pharmacokinetic techniques and assays of drug concentrations using micro-
analytic methods.
Time of plasma concentration curves of drugs after an intravenous or oral bolus
lend themselves to pharmacokinetic calculations, which reflect the events of absorp-
tion, distribution, and elimination. Absorption rate constants (ka) can be calculated
based on the method of Wagner (1) and Nelson as applied by Nortari et al. (la).
Elimination kinetics can be assessed from the log plasma concentration time curve
and from the analysis of last four points on the curve by the method of least squares
(2). Elimination rate constant (ke) and half-life (f1/2) reflect processes of elimination.
The area under the curve (AUC) can be calculated by trapezoid rule from to to tn. It
is a valuable measure of comparative bioavailability and is dependent on all the bio-
processes. Bioavailability assessment is otherwise cumbersome and unethical in
young children, since conventional methodology involves determination of a timed
plasma curve after an intravenous bolus followed by another one after an oral bolus.

DRUG METABOLISM IN PEM

Antipyrine

Antipyrine plasma half-life is inversely proportional to hepatic microsomal oxida-

tive function (26,27). It has unique properties of prompt and complete absorption
from gastrointestinal tract, rapid distribution to all fluid compartments, and insig-
nificant binding to plasma protein (28). In the liver, it is almost totally hydroxylated
to three compounds, which are excreted in the urine.
Pharmacokinetic studies in 10 malnourished children and five controls (6 months
to 5 years in age) in India (29) and in eight children (9-12.5 years) in Sudan (30)
showed that antipyrine plasma half-life was significantly increased and its clearance
rate diminished. Children with kwashiorkor had similar findings (31). There is thus
convincing evidence that hepatic mixed oxidative function is compromised in chil-
dren with PEM. This represents phase I of drug metabolizing activity. Most drugs
that are handled by the liver follow this pathway, either as a single metabolic step or
as a preparatory step for phase II. It is noteworthy that this modification of hepatic
oxidative activity is reversible by improved nutrition (29-31). In the young rhesus
monkey model, the identical pharmacokinetic situation exists. There is also dimin-
ished aminopyrine demethylase activity in the liver tissue of animals (23), suggest-
ing that a similar situation probably exists in children.

Acetaminophen

Acetaminophen, which is a widely employed antipyretic and analgesic (32), is

also rapidly absorbed from the gastrointestinal tract and distributed in all fluid com-
 DRUG METABOLISM IN MALNUTRITION 333

partments (33). Its binding to plasma proteins is insignificant. In the liver, it under-
goes conjugation by phase II reactions and is biotransformed to glucuronide and
sulfate (34,35). It is an excellent drug for studying the conjugation process, since no
preparatory phase I step is required for its metabolism. In malnourished children,
the plasma half-life of acetaminophen has been found to be increased, and its clear-
ance from the body decreased, in comparison with well-nourished children (36-38).
The excretion of its metabolites (both glucuronide and sulfate) was decreased (37).
The implications of these observations are important, not only with regard to
therapeutic applications but also with regard to adverse effects. Acetaminophen is
considered to be a relatively safe drug. At very high doses causing plasma concen-
trations greater than 120 n-m/ml, the conjugating pathways (glucuronidation and
sulfation) are saturated. An alternate pathway, which results in the formation of
acetaminophen mercapturate (39), is utilized. It appears that this intermediate me-
tabolite binds covalently to hepatic macromolecules (40) and causes hepatic ne-
crosis. In the malnourished child with a compromised capacity to carry out
biotransformation of the drug, it is possible that the conjugating pathways may be-
come saturated at lower plasma concentrations. Thus, further studies of acetamino-
phen should be undertaken before it is considered a safe drug in malnourished
children. Alteration in elimination is reversible with nutritional rehabilitation for 3
to 6 weeks (37,38).

Chloramphenicol

Chloramphenicol is a highly lipid-soluble antibiotic. Its absorption from the gas-

trointestinal tract is prompt (41,42), and its distribution to all body fluids, including
the cerebrospinal fluid, is rapid. Before elimination from the body, it undergoes bio-
transformation involving phase I and phase II reactions. The final metabolites are
glucuronides (43). The conjugation occurs inside the hepatocytes with the assistance
of the specific microsomal enzyme glucuronyl transferase.
Pharmacokinetic studies in PEM children have revealed that the plasma half-life
of chloramphenicol is significantly increased and the AUC is also increased (44).
Furthermore, its metabolites in the urine of malnourished children are much dimin-
ished (45).
Greater bioavailability, increased tm, and a lower proportion of the conjugated
drug in the urine obviously indicate that the process of biotransformation is not
functioning at full capacity in malnourished children. It is of interest that there is no
alteration in plasma protein binding in marasmus (44) or kwashiorkor (46). Delayed
clearance and higher bioavailability of chloramphenicol are likely to result in higher
plasma concentrations when administered repeatedly to malnourished children, if
the dose and the dose interval are maintained. Thus, alteration in elimination of
chloramphenicol in the malnourished child requires careful adjustment of the dosage
regimen in order to achieve effective therapeutic levels and to avoid toxic effects.
These alterations are reversible with nutritional rehabilitation.
The implications for therapeutic efficacy and toxicity are best tested by observa-
334 DRUG METABOLISM IN MALNUTRITION

tions of steady state chloramphenicol plasma levels, achieved by multiple dosing. In

one study, monitoring was performed in 35 undernourished children who received
either oral or intravenous chloramphenicol therapy for typhoid fever, bacillary dys-
entery, meningitis, or septicemia (47). There were significant differences in steady
state plasma concentrations of the drug between children with mild PEM and those
with severe malnutrition. It is noteworthy that levels achieved in children with se-
vere PEM were close to the toxic range, for both oral and intravenous groups.
From these results, it is clear that chloramphenicol should be administered in
lower than normal doses to malnourished children. The single-dose study suggests
that a therapeutically effective and safe plasma concentration can be achieved with
an oral dose of 75 mg/kg body weight or an intravenous dose of 55 mg/kg in maras-
mic children, as compared with 100 mg and 85 mg, respectively, in well-nourished
children.

Sulfadiazine

Sulfadiazine is less toxic than other sulfonamides and is extensively used in de-
veloping countries. It is rapidly absorbed from the gastrointestinal tract, and dis-
tributes itself well in body fluids (48). It is biotransformed by the process of
n-acetylation in the reticuloendothelial cells of the liver and other organs (49), re-
sulting in more water-soluble metabolites, which can be more easily excreted by the
kidney. Free parent drug can also be excreted by the kidney unchanged. Acetylation
of an HN2 group on a sulfonamide is a marker for the capacity of the N-acetyltrans-
ferase system in man. There is a genetically determined bimodal distribution of the
metabolic capacity in humans, whereby they can be classified as rapid or slow ace-
tylators. The capacity extends to several substrates, such as isoniazid, procainam-
ide, hydralazine, phenelzine, and dapsone (50).
A drug with strong genetic determinants of its metabolism requires careful inves-
tigation and interpretation when another variable such as PEM is coexistent. Our ex-
perience with sulfadiazine metabolism in young children with PEM has shown a
delay in peak plasma sulfadiazine concentration after a single oral dose of 25 mg/kg
body weight. There was a corresponding decrease in the ka. The k,. was decreased,
and plasma half-life increased, in children with PEM compared with their age-
matched controls. Correspondingly, the AUC was increased significantly in these
children (51). Excretion of "free" and acetylated sulfadiazine was estimated in 48-
hr urine collections in both groups. There was a significant decrease in the quantity
excreted as acetylated drug in the PEM group, indicating that the n-acetyltransferase
system is also affected in malnutrition.
Acetylation occurs in the presence of acetyl CoA and requires high energy phos-
phate [adenosine triphosphate (ATP)]. It is the first step in oxidative phosphoryla-
tion. In severe human undernutrition, oxygen consumption is diminished (52).
Constraint on oxygen consumption may limit the process of acetylation.
Sulfadiazine is still widely used, particularly for the undernourished children of
 DRUG METABOLISM IN MALNUTRITION 335

underdeveloped countries. Present investigations show that consideration should be

given to the fact that more of the drug is available for a longer duration in mal-
nourished children. More precise recommendations would require multidose obser-
vations.

Isoniazid

Metabolism of isoniazid is similar to that of sulfadiazine. It is acetylated by the

reticuloendothelial cells of the liver and other organs. Buchanan et al. (53) have
studied the kinetics of isoniazid in kwashiorkor children before and after nutritional
rehabilitation. These subjects served as their own controls, and genetic variation
was eliminated. Plasma half-life was increased in the acute stage of malnutrition. It
diminished after nutritional therapy when clearance rate of isoniazid improved with
the reversal of PEM. Isoniazid metabolism appears to be affected in kwashiorkor in
the same manner as sulfadiazine in marasmus.
A study of 12 malnourished tuberculous children (54) showed that oral isoniazid
was absorbed rapidly. However, most of these subjects were rapid acetylators. The
effect of malnutrition on the process of acetylation could not be clearly determined.
Clinical observations on 130 children undergoing treatment for tuberculosis with
isoniazid and rifampicin showed that 25% developed overt or subclinical hepatotox-
icity (55). The hepatotoxicity was three times more common in malnourished chil-
dren as compared with well-nourished children. The pharmacokinetics of isoniazid
in children in whom hepatotoxicity occurred on a combination of isoniazid and ri-
fampicin showed that the AUC was significantly increased (56). This is indirectly
related to the slow clearance of the drug from the body. Monitoring of antiepileptic
drugs has also shown that steady state plasma levels of phenobarbitone were higher
in children with PEM (57).
It is evident that the malnourished state of the child is intimately related to the
handling of drugs by the liver. The general effect is a prolongation of plasma half-
life and slow clearance of drugs that are metabolized by liver. It is advisable to de-
crease the dose of the drug by 25% in severely malnourished children. However,
when the nutritional state returns to normal, the dose should be restored. These are
practical guidelines. Malnourished children also require monitoring of drug therapy,
since it is not always possible to predict the overall handling of drugs in malnour-
ished children.

FUTURE RESEARCH IN DRUG METABOLISM

IN MALNOURISHED CHILDREN

The interaction of nutrition and pharmacokinetics is intimate and intricate. On the

one hand, malnutrition is associated with a multiplicity of biological alterations in-
volving almost every organ in the body. On the other hand, the handling and excre-
336 DRUG METABOLISM IN MALNUTRITION

tion of drugs are dependent on several complicated bioprocesses. The first difficulty
is in predicting any uniform pattern of disturbance. The effects of undernutrition are
heterogeneous and vary in intensity from organ to organ. The liver is involved in
varying degrees. There is no good measure to assess its functional involvement and
to use as a yardstick to predict its influence on drug metabolism. One possible tool
in this regard is antipyrine half-life, which correlates with the mixed oxidative func-
tion of the liver and hence with phase I biotransformations. There is no such mea-
sure of conjugation to enable us to assess phase II biotransformations.
There is a need for newer techniques to reflect the interaction of drugs at a tissue
level. Current methods are based on the determination of plasma drug concentra-
tions. It is presumed that the blood plasma concentration is in equilibrium with the
peripheral tissues. However, in the human clinical situation, there is lack of indica-
tors for determining drug concentrations in the tissues. The amount of drug ex-
tracted by the tissue would depend on blood flow to the organ and the affinity of the
drug for tissue proteins. Practical methods to quantify blood flow to different organs
are not available.
The information gathered on pharmacokinetics using various mathematical
models based on timed plasma concentrations of drugs does not shed light on their
action or pharmacodynamics. The tissue concentration, drug binding to tissue pro-
tein, and end-organ response are some of the determinants of organ response. This
aspect of nutrition-drug interaction awaits further investigation.

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