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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
Figure 4.6 Physicochemical and mechanical factors influencing extraoral drug absorption. Image
from vectorstock.com/1858074. Adapted by Sue Rahman and Stephani L. Stancil.
Transdermal drug delivery is employed for protracted delivery of chronic
medications (e.g., clonidine, methylphenidate, hormonal contraception). The
systemic exposure of medications applied to the skin is often increased in
infants and young children due to a more expansive body surface area (BSA)
that exhibits a higher degree of hydration and an increased extent of
perfusion.
45–47
Skin thickness has been implicated as a reason for enhanced
percutaneous absorption; however, only the preterm neonate demonstrates a
thinner stratum corneum. Neonates born at term demonstrate stratum corneum
thickness comparable to older children as do preterm newborns by 2 weeks of
age.48 While the dermis and epidermis may be thinner during the neonatal
period, the primary barrier to drug absorption (i.e., the stratum corneum) is
intact and fully developed. This potential for enhanced bioavailability needs
to be considered not only for drugs intended for systemic delivery but even
for drugs delivered with topical intent. There are countless cases of
significant and life-threatening toxicities in infants and children after exposure
to topical formulations (e.g., testosterone, other steroids, sulfadiazine, laundry
detergent, talcum powder).
49–51
Subcutaneous drug delivery has historically been used with insulin to treat
diabetes and, more recently, to delivery abortive therapy for migraines.
However, newer, protein-based biologics may also be expected to utilize this
mode of delivery. Entry into systemic circulation after subcutaneous
administration is granted through absorption into blood vessels (drug
molecules <10 nM) or lymphatic capillaries (drug molecules ~10 to 100
nM).52 Studies of insulin describe significant inter- and intraindividual
variability in subcutaneous absorption.
53,54
Though the factors influencing this
variability are not well defined, developmental changes in capillary
organization and composition of the hypodermis may play a role.
53,55–57
Finally, the intramuscular (IM) route of delivery is chosen for vaccines
and depot formulations of medications (e.g., medroxyprogesterone,
ceftriaxone). Drug is typically absorbed through the capillaries that are
perfusing the muscle. Though IM absorption is often touted as erratic in young
children, infants exhibit greater muscle capillary density compared with older
children (+25%) and adults (+56%), making this an effective means of drug
delivery in young children.
58–60
Other issues influencing the efficiency of this
route include muscle contractility, drug pKa, and solubility.
DISTRIBUTION
Once absorbed into the systemic circulation, a drug is available for
distribution throughout the body. The rate and extent of distribution is equally
dependent on the physiologic factors of the host (e.g., fraction of weight
constituted by water, circulating protein composition, expression of tissue
transporters, pH of body fluids) and the physicochemical characteristics of the
drug (e.g., molecular weight, lipophilicity, protein-binding affinity, acid–base
properties) (Fig. 4.7).
Figure 4.7 Factors influencing the rate and extent of drug distribution volume (Vd).
Developmental changes in body water stores reflect the most wellcharacterized age-dependent factor influencing drug distribution. The fraction
of total body weight accounted for by water is highest in preterm and full-term
neonates, approaching adult values by 1 year of age (Fig. 4.8). The
implication of these changes is most evident for hydrophilic drugs (i.e., those
with a Vd <0.7 to 1 L per kg) where higher weight-based doses are required in
infants and young children to achieve systemic exposures comparable to those
seen in adults. For example, infants experience peak concentrations of
gentamicin that are 33% to 50% lower than children and adults after
comparable weight-based doses.61 With their corresponding reduction in renal
clearance, infants in whom doses have not been adjusted to compensate for
the expanded volumes would eventually achieve gentamicin concentrations
equivalent to, or in excess of, adults once steady state is achieved. However,
this delay could have significant clinical consequences, given the
concentration-dependent nature of this drug.
62,63
Another example can be seen
with linezolid where distribution volume is expanded but clearance is
increased. This antibiotic demonstrates 15% to 25% higher Vd values in
neonates corresponding with 25% to 37% lower C
max
. In concert with a more
rapid rate of clearance, the drug if administered at the same weight-based
dose and dosing interval would spend only 20% to 35% of the time above the
minimum inhibitory concentration (MIC) in infants compared with 35% to
70% in children and 70% to 100% in adults.64 The impact of these findings on
the recommended dosing regimens for both of these drugs is reflected in their
labeling.
Figure 4.8 Total body weight accounted for by various compartments as a function of age.
(Reprinted with permission from Brown JT, Abdel-Rahman SM. Pediatric pharmacokinetics. Pediatric
pharmacotherapy. Lenexa, KS: American College of Clinical Pharmacy, 2013:23.)
Though neonates and infants have decreased body fat stores relative to
adults (normalizing by 2 to 3 years of age, Fig. 4.8), there is little evidence to
suggest a meaningful contribution to differences in the Vd for highly lipophilic
drugs. Such drugs are impacted, to a greater extent, by developmental changes
that influence protein binding. For highly protein-bound drugs, changes in V
d
can be clinically meaningful when the absolute amounts of plasma protein
(e.g., albumin, globulin, α-1 acid glycoprotein, lipoprotein) are reduced,
when conformational changes in the protein reduce the affinity for the drug,
and when endogenous substrates capable of displacing drugs from their
binding sites are present in the circulation.
Albumin is the most abundant protein circulating in the plasma. Acidic
drugs (those negatively charged at physiologic pH 7.4) bind almost
exclusively to albumin, while basic drugs (those positively charged at
physiologic pH 7.4) can bind to albumin as well as to other plasma proteins
(e.g., α-1 acid glycoprotein, lipoproteins). Neonates have reduced albumin
levels relative to adults, as well as isoforms of albumin with lower drugbinding affinity (e.g., fetal albumin). Neonates and young infants also
demonstrate reduced concentrations of α-1 acid glycoprotein and other
lipoproteins. Circulating levels of bilirubin and free fatty acids, which
functionally reduce protein binding via displacement of drugs from their
binding site, are also increased in neonates. Collectively, these developmental
alterations lead to reduced overall drug protein binding in the newborn and
young infant. The implications of these alterations are an increase in fraction
unbound for many drugs shortly after birth (e.g., propranolol, verapamil,
ampicillin, phenytoin, phenobarbital, thiopental, sufentanil).
65–68
Notably,
these effects can be bidirectional, where high-affinity drugs displace bilirubin
from its binding site, increasing the risk of kernicterus in the neonate.
As it is the free drug that is responsible for eliciting pharmacologic
effects, the impact of changes in protein binding is greatest for highly proteinbound drugs and, more specifically, those with a narrow therapeutic index.
One of the best examples of this principle is illustrated by phenytoin, a drug
that is 99% bound in adults. A small shift in protein binding from 99% to 98%
effectively doubles the free phenytoin from 1% to 2%. Thus, very small
changes in protein binding can significantly increase the risk of toxicity. By
contrast, a minimally protein-bound drug such as ampicillin shows small
increases in free drug available (~15%) and negligible change in risk profile
when percentage of protein bound decreases from 22% in neonates to 10% in
adults.
To our knowledge, no investigations to date have assessed alterations in
drug tissue protein binding during pediatric growth and development.
However, there have been attempts to explore differences in tissue
distribution that are driven by transporters. For many drugs, protein
transporters may represent a rate-limiting step in the overall distribution
across body tissues, regulating access to the therapeutic site of action. Due to
the limitations of experimental clinical approaches currently available to
explore tissue distribution, our understanding relies on the findings from
animal studies or human tissues collected postmortem. A study investigating
developmental expression of P-gp, MRP1, and BCRP in postmortem brain
tissues of neonates born at 22 to 42 weeks’ gestation revealed that, by late
gestation, the localization pattern is similar to that of adults; however, the
adult tissues exhibit greater quantitative expression of these transport
proteins.69 Additional investigations into P-gp ontogeny in the brain reveal
that infants between the ages of 3 and 6 months exhibit comparable levels of
this protein to adults.70 For the neonate and young infant, it is possible that
reduced expression of P-gp contributes to increased central exposure to the Pgp substrate morphine and the enhanced opioid effects observed in neonates
compared to older infants and adults.
71–73
However, this is also likely
influenced by other ontogenic changes relevant to morphine disposition [i.e.,
reduced UGT2B7-mediated metabolism, reduced hepatic uptake mediated by
organic cation transporter (OCT1)].
Other examples of transporter ontogeny that merit consideration when
discussing Vd are hepatic OCT1 and OATP1B1/3, located on the sinusoidal
membrane of the hepatocyte, that mediate the entry of drugs into the
hepatocyte. Studies of OCT1 and OATP1B3 protein expression report that
neonates and infants demonstrate significantly lower levels of these transport
proteins compared with older children, who exhibit protein levels
comparable to adults.
74,75
For OCT1, the ontogenic pattern of protein
expression is supported by lower transporter activity in pediatric versus adult
hepatocytes.35 These data may explain the age-dependent changes in the
volume of distribution for drugs that are primarily transported by hepatic
OCT1 (e.g., metformin) and may lay the foundation for further investigations
into relationships between hepatic transporter ontogeny and response for
drugs that exert therapeutic actions within the liver. However, these agedependent changes may be obscured by the contribution of genetic variations
that account for more of the interindividual variability observed with these
proteins.
74,76,77
Lastly, the distribution of drugs can also be impacted by factors
specifically associated with critically ill neonates and children.
Pathophysiologic changes such as systemic inflammation or end-organ
dysfunction may lead to a higher volume of distribution. For a child requiring
extracorporeal oxygenation (ECMO) or hemodialysis, drug adsorption to the
circuit’s tubing or membrane may lead to an observed increase in V
d
depending on the age of the ECMO circuit.78 Further studies are needed to
expand our understanding of the impact these processes have on drug
disposition.
METABOLISM
The purpose of metabolism, as it relates to drug therapy, is to biotransform an
exogenously administered substrate into a more readily excretable form. The
resulting metabolites may be wholly inactive, retain some activity, or become
pharmacologically activated. Phase I reactions are typically responsible for
oxidation, reduction, and hydrolysis of relevant substrates, while phase II
processes links the substrate with a functional group intended to increase its
water solubility. Drug metabolizing enzymes (DME) mediating
biotransformation are implicated in drug–drug, drug–nutrient, and drug–gene
interactions. Accordingly, understanding the impact of development on DME
expression and activity is important not only to anticipate changes in drug
clearance but to accurately interpret the clinical significance of potential
interactions.
The majority of drug metabolism occurs in the liver, though age-dependent
changes in liver mass, alone, do not account for ontogenic profile of most
DMEs.79 Each DME has its own developmental profile that contributes to
clearance of medications as is discussed in the following sections.
PHASE I METABOLISM
The most prominent DMEs involved in phase I metabolism are the
cytochrome P450 enzymes (CYPs). These enzymes are highly expressed in the
liver, but also expressed at lower levels in a variety of human tissue,
including the lung, oropharynx, intestine, kidney, and reproductive organs. The
most clinically relevant of these CYPs is CYP3A4, responsible for
metabolism of 30% of drugs on the market, followed by CYP2D6 and
CYP2C8/9/1980 (Fig. 4.9). Shortly after birth, a shift occurs, triggering a
steady increase in CYP3A4 expression and a decline in the fetal isoform
CYP3A7, through the first year of life. CYP3A4 activity increases to 30% to
60% of adult levels within the first week of life, with full adult values
reached by 1 year of age. Clinically relevant examples of the impact of
CYP3A ontogeny on drug metabolism exist with numerous medications (e.g.,
sildenafil, cisapride) that demonstrate marked reductions in half-life as
children mature.
14,81,82
Figure 4.9 Contribution of individual CYP450 enzymes to the metabolism of clinically used drugs.
(Adapted from Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of
gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103–
141).
CYP2D6 displays a different developmental trajectory, plateauing to adult
levels by 2 weeks of life.83 Though age may be relevant shortly after birth,
genetic polymorphisms rapidly assume the role as predominant contributors to
variability after 2 weeks. CYP2C9 displays expression and activity profiles
in microsomal samples that are similar between young infant (0 to 5 months)
and older child (5 months to 18 years); however, PK data paint a slightly
different story. The terminal half-life of phenytoin, a CYP2C9 substrate,
decreases from 20 hours at birth to 8 hours at 2 weeks of life.
84,85
Microsomal
data suggest that CYP2C19 expression and activity in vitro gradually
increases over the first 6 months of life.86 Yet, intravenously administered
omeprazole, a CYP2C19 substrate, has been found to have high clearance in
the young infant that normalizes in the first 5 years of life.
87,88
These examples
of the discrepancy between in vitro and in vivo data regarding the impact of
age on activity in the pediatric population underscore the complexity of
metabolism in the developing child and the need for substrate-specific
investigations.
CYPs that are qualitatively and quantitatively less relevant include
CYP2E1, CYP1A2, and CYP2A6. CYP2E1 is involved in the metabolism of
a variety of anesthetic agents and has shown negligible activity in the prenatal
period, increasing to 80% of adult expression and activity by the first year of
life.89 Following a similar developmental profile, CYP1A2 (contributing to
caffeine and theophylline metabolism) has minimal activity in the prenatal and
neonatal period (<4% to 5% of adult values), with gradual increase to 10% to
15%, 20% to 25%, and 50% to 55% of adult values by 1 to 3 months, 3 to 12
months, and 1 to 9 years respectively.90 The activity of CYP2A6, responsible
for the metabolism of nicotine, cotinine, and metronidazole, appears to reach
adult levels by 2 to 3 months of age; however, ontogeny in the neonate and
young infant (up to 1 to 2 months of age) is not yet well described. Examining
metronidazole as a surrogate for CYP2A6, the hydroxyl metabolite is only
present in neonates greater than 35 weeks’ gestational age and metronidazole
half-life is two to four times longer in neonates compared with adults,
91,92
suggesting negligible activity in preterm infants and reduced CYP2A6 activity
in the first 1 to 2 months after birth.
The intestinal brush border is rich with digestive enzymes and DMEs.
Individual digestive enzymes demonstrate unique developmental trajectories,
and the same is expected for DMEs.93 Pediatric intestinal biopsies
demonstrate an age-dependent increase in CYP3A4 protein expression and
activity (via 6-OH-testosterone formation) from neonate to older children.94 In
addition, CYP1A1 activity in intestinal biopsies also shows an age-dependent
effect.95 Importantly, breast-fed infants whose mothers take herbal
supplements known to alter DME activity (e.g., St. John’s wort, ginkgo
biloba) may experience sufficient exposures to alter DME activity.
96
PHASE II M ETABOLISM
Phase II metabolism is typically carried out by uridine 5-diphosphoglucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), Nacetyltransferases (NATs), and sulfotransferases (SULTs), each of which has
multiple isoforms with varying developmental trajectories.
UGT1A4, UGT1A6, UGT1A9, and UGT2B7 display activity in vitro that
is 10-fold lower in neonatal tissue compared with adult. Neonates dosed with
medications primarily metabolized by these enzymes may have reduced
intrinsic clearance.97 UGT1A1 (involved in the metabolism of acetaminophen,
ibuprofen, and warfarin as well as bilirubin) is absent in fetal liver, then
quickly ramps up expression to adult values by 3 to 6 months of life.
98
Transcript levels of UGT1A9 (involved in the metabolism of ethinyl
estradiol, ibuprofen, and acetaminophen) ramp up a bit more slowly,
demonstrating 44% and 64% of adult values by 6 months and 2 years of life,
respectively.99 UGT2B7 (responsible for 3- and 6-glucuronidation of
morphine and glucuronidation of naloxone) demonstrates differential
expression and activity with age. For example, naloxone glucuronidation was
two- to 2.5-fold lower in adolescents than adults, highlighting the continuation
of an ontogenic effect through development.97 Although typically associated
with the liver, there is considerable extrahepatic expression of UGTs with
tissue-specific levels of activity. For example, estrone conjugation by UGT is
an order of magnitude higher in the small intestine compared with the liver,
while p-nitrophenol conjugation is fivefold higher in the liver compared with
the small intestine.
100
Given their role in the metabolism of endogenous compounds such as
steroid hormones, catecholamines, and thyroid hormone, the SULTs represent
another important phase II pathway. For SULT1A1, expression profiles do not
appear to differ significantly between infancy and adulthood. SULT2A1, by
contrast, demonstrates a significant increase in activity from birth to 3 months,
when values equal those seen in adults.
101
Interestingly, protein expression of
SULT1E1, an enzyme responsible for estrogen inactivation, declines from
fetal life to adulthood.
GSTs are responsible for glutathione conjugation of cisplatin, busulfan,
and endogenous compounds, such as leukotrienes and prostaglandins.
102
GST1
reaches adult expression levels by 1 to 2 years of age.
103
However, GSTA1
and GSTA2 are present in fetal liver and increase 1.5- to twofold at the time
of birth without evidence of significant further increase through adulthood.