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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
gene and protein expression is accomplished by measuring messenger RNA
(mRNA) and protein content, respectively, whereas protein activity is
determined via direct measurement of drug biotransformation or transport.
Notably, correlations between transcript copy number, protein levels, and
functional protein activity range from poor to strong. Thus, mRNA and protein
levels are inconsistent surrogates for protein function. Nevertheless, their
expression profiles can still offer insight into age-dependent changes that may
influence the disposition of drugs that serve as substrates for these proteins.
As exemplified in the sections below, human, animal, and in vitro studies are
often used in a complementary manner to paint a comprehensive picture of the
impact of ontogeny on drug disposition.
ABSORPTION
Generally speaking, absorption is defined as the process by which drugs pass
into the intravascular space (systemic circulation) from the site of application
or administration. Bioavailability, more specifically, describes the extent to
which unchanged drug enters the systemic circulation. For drugs administered
by routes other than parenteral, both the rate and the extent of absorption are
influenced by physicochemical and mechanical processes that are susceptible
to age-dependent influences.
ORAL ADMINISTRATION
A sample of processes that impact oral absorption is detailed in Figure 4.1.
However, all of these presuppose that the drug has passed through the oral
cavity, not a guarantee in children. It is not uncommon for children to reject
medications based on taste, smell, or texture, each of which demonstrates a
unique developmental trajectory. The capacity to discriminate sour, salty, and
bitter appears to mature around the age of 2 years preceded by texture,
temperature, and piquancy at 1 to 2 years and sweet and umami which actually
appear to be present in utero. Olfactory development, by contrast, does not
fully mature until a child reaches 5 to 7 years of age.
3–5
These teleologic
drivers influence a child’s willingness to accept newly introduced foods and,
by extension, medicines. Consequently, thoughtful consideration of a child’s
age or age group is necessary when making therapeutic decisions, or
designing masking strategies, for drugs with aversive palatability
characteristics for no drug that fails to make it past the oropharynx will be
effective.
Figure 4.1 Physicochemical and mechanical factors influencing oral drug absorption.
Immediately past the oral cavity, the drug encounters the stomach which,
for many drugs, serves as the site of disintegration and dissolution. Whereas
the gastric milieu is highly acidic in the adult (pH ≤3), a combination of
factors contributes to higher gastric pH in neonates and young infants. These
include reduced hydrochloric acid production (despite a state of relative
hypergastrinemia) and increased feeding frequencies where food contents
effectively buffer the gastric fluid. As the stomach is not the primary site of
absorption for orally administered drugs, the impact of altered pH on the
ionization state of drugs holds limited relevance.
6–8
More important is the
impact of gastric pH on the stability of drug. With an elevated pH, acid-labile
drugs (e.g., β-lactam antibiotics) are afforded an element of protection,
making more of the drug available for absorption. Figure 4.2 illustrates this
phenomenon, showing that comparable weight-based doses of penicillin
demonstrate five to six times higher concentrations in newborns compared
with older infants and children.9 These findings can be extrapolated to other
acid-labile drugs not otherwise formulated in a manner which protects the
active compound from gastric acid. These pH differences can also impact
formulations designed to liberate their contents under selected physiologic
pH. Those designed to release drug in an acidic environment may exhibit
incomplete or delayed release profiles in younger children,10 whereas those
designed to release their contents at the more basic intestinal pH may
experience faster release characteristics in this population.
11
Figure 4.2 Impact of age on weight-based dosing of penicillin. (Reprinted with permission from
Brown JT, Abdel-Rahman SM. Pediatric pharmacok inetics. Pediatric pharmacotherapy. Lenexa,
KS: American College of Clinical Pharmacy, 2013:19.)
From the stomach, drugs migrate into the intestines where the time
required for emptying of the gastric contents and motility along the intestinal
lumen can influence the rate of drug absorption. Owing to irregular peristaltic
activity at the time of birth, the rate of gastric emptying and intestinal transit is
prolonged in the first few days of life, but quickly approaches adult values
within weeks to months.
7,12,13
Consequently, it is not unusual to see slower
absorption rates and delayed T
max
for selected drugs during this time frame.
7,14
Since these physiologic changes normalize relatively quickly after birth, the
physicochemical properties of a drug (i.e., solubility and permeability) should
more heavily influence absorption profiles after the first month of life. Other
contributors to altered rates of drug absorption in children that persist beyond
the first month of life include underlying disease (e.g., prematurity,
respiratory, gastroesophageal, congenital heart disease) and diet.
15
In contrast to intestinal transit, age-dependent differences in the maturation
of intestinal structures are not expected to negatively influence drug
absorption rates in children. Finger-like projections of villi populating the
intestinal wall immensely expand intestinal surface area, making it the
primary absorptive site for orally administered drugs. Importantly, these villi
and their corresponding microvilli are essentially fully mature by 20 weeks of
gestational age.
16,17
In addition, intestinal length relative to body length is
greater in neonates and children as compared with adults (Fig. 4.3).
Consequently, the available absorptive surface area for drugs in the intestine
of children is comparable to or greater than that of adults when adjusted for
size.
Figure 4.3 Anthropometric data relative to adult values as a function of age. (Reprinted with
permission from Brown JT, Abdel-Rahman SM. Pediatric pharmacok inetics. Pediatric
pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy, 2013:20.)
Despite the rapid maturation of intestinal motility and expanded intestinal
surface area early in life, absorption rates for some passively absorbed
compounds still demonstrate delays through the first 3 to 6 months of life.
7
The iatrogenic administration of prokinetic agents can enhance absorption
rates in young infants, but not to the extent experienced by older infants,
suggesting that additional factors contribute to slower rates of absorption in
young infants7 (Fig. 4.4). Though not well characterized, other explanations
may include alterations in splanchnic blood flow. In both preterm and fullterm neonates, preprandial mesenteric blood flow volume increases markedly
over the first few weeks of life.
18–20
Whether this can be offset by the changes
in splanchnic blood flow that accompany the increased feeding frequency at
this age is unclear.
21,22
Figure 4.4 The impact of metoclopramide, a prokinetic agent, on the rate of absorption in neonates
versus older infants. (Adapted from Heimann G. Enteral absorption and bioavailability in children in
relation to age. Eur J Clin Pharmacol 1980;18:43–50.)
The extent of oral absorption can also be influenced by maturational
changes occurring in tissues and organs affiliated with the intestine. Through
the first 6 months of life, postprandial sampling of two major bile salts
demonstrates high circulating plasma concentrations, yet lower concentrations
in the intestinal lumen as compared with older children and adults. This is
likely the consequence of an immature bile salt transport mechanism.
23–27
The
pharmacologic relevance is a reduced capacity for the absorption of drugs
that require solubilization by bile acids prior to absorption. The impact can
be seen in the example of pleconaril, a highly lipophilic antiviral, where dose
escalation in adults is accompanied by a dose-proportional increase in total
body exposure, yet dose escalation in neonates fails to show increase
exposure.
28,29
The lipid-based chloramphenicol palmitate serves as another
example30 as do the dietary fatty acids, palmitate and stearate, for which
absorption increases steadily through the first 3 to 4 months of life.
31
TABLE 4.2
Role of the Microbiome on Oral Absorption
Although the biology and function of the microbiome, particularly in neonates
and children, has yet to be fully described, its impact on drug absorption
cannot be discounted. An infant’s mode of delivery (e.g., vaginal vs.
Cesarean) and diet are two factors that contribute to the composition of the gut
microbiome fostering the diversity that appears to increase with age.
32,33
These organisms can play a role in drug biotransformation, including
conversion of orally administered drugs into metabolites with different
activity profiles and deconjugation of enterohepatically recycled compounds
liberating an active moiety for reabsorption. Digoxin offers one example of
the impact that age-dependent changes in the microflora have on drug
disposition. Anaerobic bacteria, which predominate in adult intestines,
mediate the inactivation of digoxin into digoxin reduction products (DRPs).
The recovery of DRPs in the urine of patients receiving digoxin increases
steadily from birth to adulthood, with the biggest increase seen near the time
of weaning. This occurs in concert with an increase in the presence of DRP
forming bacteria in stool.34 Because of the complexity of factors influencing
the composition of the intestinal microbiome, the full impact of developmental
trajectories of the microbiome on drug absorption has yet to be elucidated.
Role of Transporters in Oral Absorption
Drug transporters that reside in the membrane of intestinal epithelial cells
localized either apically (i.e., facing the gut lumen) or basolaterally (i.e.,
facing the gut vasculature) can also contribute to age-dependent changes in
drug disposition. The primary role of intestinal transporters, as it relates to
drug disposition, is to modulate the transcellular passage of drugs from the gut
lumen to the presystemic circulation by either facilitating or preventing the
process. This is particularly important in the disposition of drugs that
demonstrate poor passive diffusion characteristics (i.e., those that are large,
hydrophilic, and charged at intestinal pH). The two major superfamilies
present in the intestines include the ATP (adenosine triphosphate)-binding
cassette (ABC) family or the solute carrier (SLC) family (Table 4.2).
Clinically Relevant Drug Transporters
The ontogeny of transporters is typically assessed via measurement of
mRNA or protein expression in human pediatric biopsy tissues, postmortem
human tissues, or animal models. A fairly robust example of intestinal
transporter ontogeny is available with permeability glycoprotein (P-gp). The
absence of detectable mRNA levels during the first 12 weeks of gestation are
followed by measurable and stable mRNA expression after the completion of
the first trimester (i.e., >12 weeks’ gestation). Limited data suggest that adult
levels of expression are reached at, or shortly after, birth. Not unexpectedly,
these investigations also document marked interindividual variation in P-gp
expression.35 Multidrug resistance protein 2 (MRP2) is similarly detected in
neonatal tissue, appearing constant through adulthood and characterized by
marked interindividual variation.35 Expression and cellular localization of the
transporter, breast cancer resistance protein (BCRP), was detected as early as
5.5 weeks of gestation and remains unchanged up to 28 weeks. P-gp, MRP2,
and BCRP are located on the apical membrane and function as efflux
transporters restricting the passage of a drug into an intestinal epithelial cell.
The organic anion transporting polypeptide 2 (OATP2B1) is also located
apically, but functions as an uptake transporter by facilitating drug or solute
entry into the intestinal epithelial cell. Significantly higher levels of
OATP2B1 mRNA are detected in neonates than in adults, suggesting that
levels decrease as the child develops.
35
Although less frequently available, the strongest evidence for
developmental patterns of intestinal transporter activity is provided by studies
that utilize probe transporter substrates. For example, a study examining agedependent changes in the PK of the H2-receptor antagonist, nizatidine, reveals
a clear age-dependent reduction in apparent oral clearance unaccompanied by
a change in the elimination rate constant. The authors hypothesize that this
finding may be accounted for by age-dependent expression of the
transporter(s) that mediate translocation of the drug into the presystemic blood
circulation.36 Other studies allude to age-dependent differences in intestinal
transporter expression by examining nutrient uptake. Iron absorption, for
example, mediated by the divalent metal transporter 1 (DMT1), increases
linearly with age, attaining adult levels in early childhood
37,38
(Fig. 4.5).
Figure 4.5 Enteral iron absorption as a percentage of the dose administered. (Adapted with
permission from Gladtke E, Rind H. Iron therapy during childhood. Ger Med Mon 1966;11:438–442.)
It is important to recognize that current data suggest no single, unified
developmental pattern of intestinal transporter expression in children. It is
also important to point out that age-dependent changes in feeding frequency
and composition can alter the expected activity of intestinal transporters. For
example, the consumption of milk-based feeds delivered every few hours in
the young infant may interfere with the uptake of substrates for intestinal
peptide transporters (e.g., PEPT1),39 and the exceedingly large quantities of
apple juice consumed by young children can influence the uptake of substrates
for organic anion-transporting polypeptides. The extent to which these
interactions are relevant in children will largely depend on the level of
expression for these and other transport proteins.
EXTRAORAL ADMINISTRATION
The rate and extent of extraoral drug absorption is similarly affected by
physicochemical and mechanical factors that are susceptible to age-dependent
changes (Fig. 4.6). Rectal administration is favored for the delivery of drugs
to children when oral or intravenous routes are unavailable or
contraindicated.
40–42
Unless delivered as a rectal solution, the absorption of
rectally administered drugs depends on the characteristics of the formulation
and the age of the child. Slow-melt suppositories, for example, will likely be
expelled before releasing the entirety of their drug contents in young infants
who experience far more high-amplitude pulsatile contractions of the lower
gastrointestinal (GI) tract than do older children or adults.
40–44