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S E C T I O N
II
Pharmacology in Special
Settings and Population: The
Newborn
Jamil M. Kazma
Johannes N. van den Anker
Karel Allegaert
André Dallmann
Homa K. Ahmadzia
C H A P T E R
9
Role of Placenta in Drug Metabolism and Drug Transfer
INTRODUCTION
The placenta is an ephemeral organ that is pivotal for the development of the
fetus.
In some cultures, it is believed that burying the placenta after birth
reinforces the baby’s belonging to earth. Since the 16th century, in its
powdered form “Placenta Hominis,” the placenta has been used in traditional
Chinese medicine to treat a myriad of symptoms.1 The ground-breaking work
of Mossman, published in 1937, on the developmental comparison of the
placenta across species,2paved the way for more sophisticated delineations of
its anatomic and physiologic architecture. He simplified the definition of the
placenta as “fusion of the fetal membrane to the uterine mucosa for
physiologic exchange.”
The placenta’s growth from a few cells into a multifunctional organ is
unmatched by any other organ. It serves as an interface connecting the mother
and fetus. However, the wording “placental barrier” holds a false notion since
the placenta is the entry through which the fetus is exposed to compounds as
well as the exit to eliminate compounds. In addition, it plays an important role
in the synthesis of hormones (progesterone, estrogen) and peptides (human
chorionic gonadotropin, placental growth hormone, insulin growth factor) that
are vital for a successful pregnancy, while its dysfunction has been associated
with preeclampsia.
3–7
Furthermore, the placenta has metabolic functions,
including metabolic processes related to medicines, like for some steroids.
The “barrier” or “filter” function of the placenta includes passive diffusion,
facilitated diffusion, active transport, and pinocytosis/endocytosis.
7
Historically, it took several articles
8–10
to discredit the notion that the
placenta is an impermeable barrier against xenobiotics. Some reasons that
corroborated the original belief of impermeability were the perceived
idealization of the womb and a general disinterest in stillborn outcomes.11 It
was not until the thalidomide disaster in 1961 that the scientific community
embraced the fact that the placenta is a permeable barrier to molecules and
drugs, some of which can result in fetal teratogenicity.
12,13
Since then, it has
been the target of research despite the countless challenges accompanying it.
Understanding the underlying mechanism of the transport of drugs and
molecules across the placenta and its physiology is essential in paving the
way for experiments conducted by researchers and pharmaceutical companies
to unravel the real mystery of this interface and improve our understanding of
pharmacotherapy in pregnancy.
This chapter reviews the function of the placenta in drug transfer, focusing
on the mechanisms and factors that mediate it. In addition, the chapter expands
on the biotransformation and metabolism of compounds that cross the
placenta, highlighting the enzymes and chemical reactions involved.
ANATOMY OF THE HUMAN PLACENTA
There is extensive variability in the placenta among different species. This
variability is based on the four categories: shape, placental interdigitation,
maternal–fetal interface, and the arrangement of the maternal and fetal
circulation.14 The human placenta is of discoid shape, which provides the
lowest surface area.15 As for the placental interdigitation in humans, it is best
described as villous, which may offer a metabolic advantage in requiring less
energy and thus the ability to sustain a longer gestation.16 The human placenta
is of the hemochorial type where one syncytiotrophoblast layer is in direct
contact with the maternal blood and is the most intimate form.17 The
predicament of this type of interface is that it is dependent on the development
of tolerance in the maternal immune system to the paternal antigens present on
the placenta.18 The difference in the anatomic structure of the placenta among
animal species complicates the design of animal experiments to study human
diseases.
14
The placenta, on average, measures approximately 22 cm in diameter and
weighs about 470 g at delivery19; however, the weight may vary at term, with
a median of 475 g at 37 weeks to 515 g at 40 weeks, and by disease status,
such as in the case of pregnancy in women with diabetes.20 Also, it is
polarized with two plates, the basal plate, which is in contact with the uterine
endometrium and maternal circulation, and the chorionic plate to which the
umbilical cord attaches.
19
At implantation (day 6), the trophoblast cells, surrounding the inner cell
mass at the embryonic pole of the blastocyst, interact with the epithelial cells
of the endometrium. This interaction triggers the remodeling of the
extracellular matrix of the endometrium and the interweaving of the
syncytiotrophoblast (multinucleated cells of the trophoblast) between
endometrial cells. As a result, the arterioles and capillaries are eroded,
allowing maternal blood to perfuse to what is referred to as the intervillous
space,
21,22
eventually surrounding the conceptus where the blastocyst is
covered with maternal blood, forming the trophoblastic lacunae.
23,24
This
intervillous circulation is not evident until 9 weeks and becomes continuous
across the placenta by 12 weeks of gestation.25 The placenta thus develops in
a low O2 milieu, which minimizes the production of reactive oxygen species
that has been linked to causing damage to the syncytiotrophoblast.
26
The cytotrophoblasts (unicellular cells of the trophoblast) covered with
syncytiotrophoblast cells penetrate the lacunae to form the primary villi and
subsequently differentiate to the anchoring villi as they reach the uterine
decidua.27 These differentiated villi are made up of two cell lineages:
cytotrophoblast and syncytiotrophoblast. The basic structure of the placenta is
complete by 4 weeks of gestation. The syncytiotrophoblast layer is also
polarized with a maternal-facing brush border membrane (apical) and fetalfacing (basal) membrane that share different molecular compositions. In
addition, the syncytiotrophoblast layer is continuous, whereas the underlying
cytotrophoblast is discontinuous.
28,29
It is important to note that normally
maternal and fetal blood do not mix directly, but exchange of nutrients and
drugs occurs across these various cellular layers (Fig. 9.1).
Figure 9.1 Normal anatomy of the maternal–fetal placental interface and overview of important
transport mechanisms across the placenta. BRCP, breast cancer resistance protein; MATE1, multidrug
and toxin extruding protein 1; MDR1, multidrug-resistant protein 1; MRP1, multidrug resistanceassociated protein 1; MRP2, multidrug resistance-associated protein 2; OAT4, organic anion transporter
4; OATP4A1, organic anion transporting polypeptide 4A1; OATP2B1, organic anion transporting
polypeptide 2B1; OCT1, organic cation transporter 1; OCT3, organic cation transporter 3; OCTN1,
organic cation/carnitine transporter 1; OCTN2, organic cation/carnitine transporter 2; Question marks
indicate transport process required characterization. (Reprinted with permission from Al-Enazy S, Ali S,
Albekairi N, et al. Placental control of drug delivery. Adv Drug Deliv Rev 2017;116:63–72.)
MATERNAL PHYSIOLOGIC CHANGES IN
PREGNANCY
TABLE 9.1
Pregnancy results in notable physiologic changes to the maternal body and
placenta to accommodate the metabolic demands of the mother and the
growing fetus. Several of these changes may affect variables governing
pharmacokinetics of drugs, including absorption, distribution, metabolism,
and excretion.30 Among the most critical changes is an increase in plasma
volume, which is first evident around 6 to 8 weeks, and continues to increase
with a peak around the 32nd week of gestation.
31–33
This expansion leads to an
increased volume of distribution of hydrophilic drugs, similar to the increase
in fat mass in pregnancy and its effect on lipophilic drugs. In addition, the
blood flow to the uteroplacental circulation reaches its peak in the third
trimester, ranging from 50 to 60 mL per minute at first trimester to the peak of
185 mL per minute before hitting another peak at term reaching between 450
and 750 mL per minute.
34–36
The proportion of the cardiac output flowing into
the uteroplacental circulation at early pregnancy also increases from 3% to
6% to about 12% at term.
35,36
Furthermore, the concentration of albumin, an important protein carrier of
many drugs, decreases by 25% as pregnancy progresses, causing drugs that
are highly protein bound to have a higher concentration of the unbound
form.
37–40
Another binding protein for many basic drugs, α-1 acid
glycoprotein, also decreases by 15% by the third trimester.
40,41
Changes in the gastrointestinal tract, including decreased gastric pH,
increased volume of gastric secretions, and a relaxed esophageal sphincter
tone, not only contribute to increased nausea and vomiting but may also affect
the absorption and bioavailability of oral drugs.
42,43
Despite controversy as to
whether there is a decrease in gastric motility during pregnancy across
different studies,
44,45
theoretically, these hormonally induced changes would
decrease the peak concentration of oral drugs in the maternal circulation.
46
Moreover, the liver enzymes responsible for phase I and phase II metabolism
are altered in pregnancy.
47,48
These enzymatic alterations may affect drug
clearance and excretion, which in response may require dose adjustments for
certain drugs. Renally cleared drugs can be particularly affected as pregnancy
causes an increase in renal plasma flow and glomerular filtration rate.
49,50
Table 9.1 summarizes the key physiologic changes during pregnancy.
Major Pharmacokinetic Change s during Pregnancy
Change in Pregnancy Pharmacokinetic Effect Potential Clinical Effect
Increased body weight Lower serum concentrations Smaller effects if dose not
increased
Lower serum albumin levels Higher free (unbound) fraction
leads to greater transport,
clearance
No change in the steady-state
concentration of the free drug
(e.g., phenytoin)
Increased hepatic metabolic
rate
Faster clearance rate of some
drugs metabolized by the liver
Smaller effects if the dose is
not increased; for example,
dexamethasone is not
metabolized in the liver and
hence is more likely to cross
the placenta at higher
concentrations
Decreased hepatic metabolic
rate
Slower clearance rate For example, theophylline
metabolized more slowly
Higher liver blood flow Faster clearance rate of high-
extraction ratio drugs
Smaller effects if dose is not
increased
Higher glomerular filtration rate Faster clearance rate of renally
excreted drugs or their active
metabolites
Smaller effects if dose is not
increased (e.g., lithium, digoxin)
Lower compliance (because of
fears of teratogenicity)
Lower drug concentrations More therapeutic failures
Data from Koren G, Klinger G, Ohlsson A. Fetal pharmacotherapy. Drugs 2002;62(5):757–773 and
Loebstein R, Lalkin A, Koren G. Pharmacokinetic changes during pregnancy and their clinical
relevance. Clin Pharmacok inet 1997;33(5):328–343.
The placenta itself undergoes physical changes during pregnancy. The
placental barrier thickness decreases by up to 95% from late first trimester to
term, the surface area increases by 140% from the late second trimester to
term, and the cytotrophoblast layer becomes more discontinuous as the
pregnancy progresses.
51–53
Moreover, placental transport and exchange is
altered as pregnancy progresses, shifting from histotrophic nutrition under
anaerobic conditions during first trimester to supplementation by maternal
arterial circulation that perfuses the intervillous space for the remainder of the
pregnancy.
54–56
Gestational-specific uterine perfusion to the placental
compartment increases by about 12-fold at term.43 However, there is limited
information on whether there is a change in placental drug transport with
gestation.57 The complexity of placental and physiologic changes during
pregnancy makes it challenging to conduct clinical drug trials to identify
optimal dosing regimens. In addition, concerns about fetal safety hinder
further advancements in this field.
MECHANISMS OF PLACENTAL TRANSFER
OF DRUGS
Transplacental therapy has been a low-profile research field for some time.
Decades ago, Ampola and colleagues were the first to treat methylmalonic
acidemia of a fetus by administering large doses of vitamin B12 to the
mother.58 More recently, transplacental therapy has been used to treat several
fetal disorders, including fetal arrhythmias, human immunodeficiency virus
(HIV) mother-to-child transmission, fetal lung maturity, and passive fetal
immunity.59 Also, fetomaternal alloimmune thrombocytopenia can be managed
by giving intravenous immunoglobulins (IVIgs) to the mother, saturating the
receptors on the placenta, and preventing further transfer of the antibodies
targeting platelets across the syncytiotrophoblast membrane and into the fetal
circulation.60 In addition, drug therapy can target placental dysfunction such as
the case of sildenafil used in the management of early-onset fetal growth
restriction and preeclampsia; a promising but experimental therapy so far.
61
Endogenous and exogenous compounds may cross the placenta to various
degrees and are best characterized as an unequal bidirectional transfer. The
crossing is governed by several factors intrinsically related to the nature of
the compound and the need for transport shuttle and energy expenditure across
the syncytiotrophoblast, the basement membrane, and the endothelium of fetal
capillaries.51 Maternal diseases such as preeclampsia may also affect
placental drug transfer in ex vivo models.61 An increase in oxidative stress
seen in conditions such as fetal growth restriction, diabetes, and preeclampsia
may also affect the transport of nutrients and the permeability of the
membrane.62 With the advancements in transplacental pharmacokinetics and
the need to have accurate and safe pharmacotherapy during gestation, it
became important to understand the function and expression of transport
proteins and drug interaction at this interface.
CHEMICAL AND PHYSICAL FACTORS AFFECTING
PLACENTAL TRANSFER
Size
Any molecule with a molecular weight (MW) of more than 1,000 Da rarely
crosses the placenta, those with MW of less than 500 Da generally cross
readily, and the remaining cross at a slower rate.63 This property does not
limit transport, however, as most drugs are less than 500 Da, except e.g. for
the various forms of heparin, which are known not to cross the placenta.
64
Insulin (5,734 Da) is another example where the placenta is an effective
barrier against its transport.
65
Blood Flow
For lipophilic drugs, the blood flow is critical in determining the rate of
exchange across the placenta. It limits the availability of the drug at the
interface, making them flow limited, as opposed to the hydrophilic drugs,
which are permeability limited.66 Any change from the maternal blood flow
(uterine) and fetal blood flow (umbilical), such as hypertensive disorders in
the mother or severe cardiac insufficiency in the fetus (like fetal end-diastolic
reversed blood flow), may result in an altered drug exposure and thus affect
the diffusion rate.
67,68
During labor and delivery, the decrease in blood flow to
the placenta due to regular uterine contractions may contribute to a delay in
the clearance of drugs already in the fetal circulation and affect the delivery of
the drug from maternal circulation.
66
Protein Binding
Protein-bound drugs cannot readily cross the placenta. Two essential plasma
proteins are responsible for the majority of protein binding of drugs, albumin
and α-1 acid glycoprotein, which, generally speaking, bind acidic and basic
drugs, respectively.
69,70
Valproic acid, for example, binds to albumin,
71
whereas drugs such as cocaine and sufentanil, both weak bases, bind
predominantly to α-1 acid glycoprotein. Diazepam, a weak base, does not
comply with the general rule as it is shown to bind albumin.72 Bupivacaine, a
common anesthetic used in spinal anesthesia for cesarean delivery, is highly
protein bound to albumin.73 Both α-1 acid glycoprotein and albumin
concentration decrease in pregnancy, yet albumin does so at a far greater
degree.39 In the fetus, the concentration of both albumin and α-1 acid
glycoprotein increases from the first trimester until term, but α-1 acid
glycoprotein concentration in the fetus reaches only 50% of that found in
maternal blood.
66,74
This differential translates into having more unbound
drugs readily available to cross the placenta across the gradient. Propofol is a
highly protein-bound drug to albumin and red blood cells, and its placental
transfer is affected by both increased maternal blood flow and decreased
albumin concentration, such that there is an increased uptake by the placenta
and transfer to the fetus.75 The use of propofol has been associated with lower
Apgar scores at 1 and 5 minutes compared to thiopental, when used for
induction of anesthesia in cesarean delivery.76 However, in other studies, this
has not shown to be true.
77,78
This phenomenon of protein binding is subject to
competition by endogenous molecules like free fatty acids, which are three
times higher in the mother compared to fetal concentration at term. However,
the saturation of proteins like albumin by free fatty acids is negligible when
compared to the protein concentration effect on the placental transfer of
drugs.
79–81
pH and Ion Trapping
A drug cannot pass the placental barrier in its ionized or charged form. Most
drugs are either weak acids or weak bases, which cause them to be charged at
physiologic pH. The maternal pH (pH = 7.4) is higher than fetal pH (pH =
7.3) by 0.1 log units, allowing the fetal concentration of basic drugs to exceed
the maternal concentration at equilibrium.82 Clinically, this is important to
consider during fetal acidemia, as fetal pH decreases further, allowing for
more basic drug accumulation such as lidocaine, bupivacaine, and other
amide anesthetics during delivery, possibly leading to neonatal side effects.
83–
8
Neerheles, studieshve shown that the phenomenon of ion trapping merely
contributes as a sole factor for controlling placental transfer. Weak acid drugs
such as salicylates and valproate, which are ionized at physiologic pH,