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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
metabolic genes, particularly that of CYP1A1 and GSTT1, which, in turn, are
associated with the pathogenesis of low birth weight in mothers who
smoke.
191,192
CYP1A1 is induced by polycyclic aromatic hydrocarbons and
other environmental pollutants present, leading to the creation of DNA
adducts in the placenta.
193
Of particular interest in this enzyme is the fact that
it is inducible under the aryl hydrocarbon receptor (Ah receptor) activity,
which is abundantly present in the placenta.
194,195
This enzyme has a low level
of activity at baseline but is inducible in smoking mothers. Its activity is
highest at the end of pregnancy.
185,196
The role of this enzyme in mediating fetal
toxicity from smoking, such as intrauterine growth restriction, has not been
explored yet.
197,198
However, mothers who smoked cigarettes and delivered
low birth weight babies had a higher activity of placental aryl hydrocarbon
hydroxylase (an indicator of high activity of CYP1A1) and thus are at
increased risk of having DNA adducts.
199–201
Interestingly, patients who
delivered infants with anencephaly had a lower activity of CYP1A1 and the
activity of this enzyme was lower in older mothers, suggesting that the activity
of this enzyme may explain the association of fetal abnormalities with
advanced maternal age.
172,202
Cytochrome P450 CYP3A Family
This particular group of metabolic enzymes is the most commonly expressed
drug metabolizing enzyme in the liver.
203
Its expression in the placenta has
been studied; however, its contribution to metabolism of drugs is limited.
66
CYP3A in the placenta may play a role in the teratogenicity of thalidomide.
204
Glyburide is another substrate that is metabolized by CYP3A7 in the fetal
liver. However, metabolism of drugs by placental CYP3A7 is poorly
understood.
205,206
PHASE II BIOTRANSFORMATION
Uridine 5′-diphosphate Glucuronosyltransferase
The fetoprotective role of the uridine 5′-diphosphate glucuronosyltransferase
(UGT) enzymes is to conjugate glucuronic acid to the drug, increasing its
polarity and thus enhancing its excretion.
207
There are more than 15 isoforms
that are present ubiquitously throughout the pregnancy with high
interindividual variability.
208
Olanzapine is an example for a UGT1A4
substrate, whereby the drug is partially converted into its glucuronide
conjugate, which has a lower rate of transfer across the placenta compared to
its parent compound due to placental UGT1A4 metabolism.
209
Lamotrigine is
metabolized by UGT1A4, which may explain why its level may fall in
pregnant women and dose adjustments are necessary to achieve optimal
therapeutic effect.
210
Glutathione-S-Transferases
The glutathione-S-transferase (GST) is responsible for the conjugation of a
glutathione group to compounds, diminishing their toxicity. The only isoform
in the placenta is the GST-π, and this is present throughout the pregnancy.
211
Its
role in the detoxification of drugs in the placenta is not clear. However, it is
implicated in hormone metabolism and may play a role in protecting the fetus
from oxidative stress.66 Fluoxetine, an antidepressant, and its metabolite can
inhibit the GST-π in the placenta, exposing the fetus to unknown electrophiles
and toxins.
212
In addition, mutations in other forms have been associated with
an increased risk of unexpected recurrent pregnancy loss, suggesting an
important role of detoxification for this enzyme early in pregnancy.
213
Others
The role of sulfotransferases in drug metabolism is not well known. However,
it is a crucial enzyme in the process of estrogen production, removing the
sulfate group from estrone sulfate and from 3β-hydroxysteroids.
214,215
The
epoxide hydrolase enzyme is responsible for transforming epoxides into transglycols or trans-dihydrodiols.
216
Epoxide metabolites of anticonvulsant drugs
(e.g., phenytoin) are known to be associated with the pathway of
teratogenicity and fetal hydantoin syndrome. However, little is known about
the role of the placental epoxide hydroxylase in the detoxification
process.
214,215
TERATOGENICITY OF DRUGS
TABLE 9.2
The critical period of pregnancy for teratogenic effects is organogenesis
between the third and eighth week of gestation; however, other developmental
toxicity may occur after the first trimester. Major malformations, particularly
anatomic, can arise in that period due to drug exposures or other exogenous
compounds. Exposure to drugs later on in pregnancy may induce malformation
that affects neurobiologic development.
217
Fetal exposure to drugs is
dependent on the fetal concentration, which is, in turn, a factor determined by
maternal concentration. However, the toxicity due to a drug may be from the
direct exposure of the drug or perhaps other secondary consequences due to
the drug exposure. For example, one theory highlights misoprostol-associated
Moebius syndrome secondary to uterine contractions, instead of direct effects
on the fetus.
218
Another theory linked misoprostol-associated congenital
abnormalities in early pregnancy to its vasoconstrictive effects.
219
The
importance of identifying teratogenicity comes into play during physician
counseling and selection of pharmacotherapy. Especially in the era of
advertising new pharmacotherapy, this is a developing field and postmarket
surveillance of adverse effects aids in available data. However, limited case
reports or series in humans, if any data in humans at all, are often referenced
by online platforms, such as Reprotox.org. Table 9.2 provides a list of
common drugs and their teratogenic effect on fetal development.
Drugs with Proven Teratoge nic or Other Adverse Effects in Humans
Drug Teratogenic Effect
Aminopterin, methotrexate Skull and limb malformations
Angiotensin-converting enzyme
inhibitors
Prolonged renal failure in neonates, skull dysgenesis, Potter
sequence
Carbamazepine Neural tube defects
Danazol and other androgenic drugs Masculinization of the female fetus
Diethylstilbestrol Vaginal carcinoma and other genitourinary defects in
female and male offspring
Hypoglycemic drugs Neonatal hypoglycemia
Lithium Heart defects
Mycophenolate mofetil Microtia, cleft lip/palate, hypoplastic fingers and toenails,
heart defects, micrognathia
Misoprostol Moebius sequence
Nonsteroidal anti-inflammatory drugs Constriction of the ductus arteriosus, necrotizing
enterocolitis, oligohydramnios
Paramethadione Facial and CNS defects
Phenytoin Growth restriction, CNS and heart defects
Psychoactive drugs (e.g., barbiturates,
opioids, benzodiazepines)
Neonatal withdrawal syndrome when a drug is taken in late
pregnancy
Systemic retinoids (isotretinoin,
etretinate)
Craniofacial, cardiovascular, and other defects related to
neural crest migration failure
Tetracycline Discolored teeth, hypoplastic fibula
Thalidomide Phocomelia (limb-shortening defects), internal organ
defects, autism
Trimethadione Facial and CNS defects
Valproic acid Lumbar meningomyelocele, limb defects, cognitive
impairment, autism
Warfarin Cartilage hypoplasia, porencephaly
CNS, central nervous system.
Data from Briggs GG, Freeman RK, Towers CV, et al. Drugs in pregnancy and lactation: a
reference guide to fetal and neonatal risk, 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins,
2017 and Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998;338(16):1128–1137.
STUDYING DRUG TRANSFER ACROSS THE
PLACENTA
With the advancement of technology and the expanding research in the field of
pharmacotherapy in pregnancy, researchers are facing the predicament of
extrapolating data from animal studies to the human species in addition to the
limited inclusion of pregnant women as human subjects in pharmacology
clinical trials. In the past 60 years, more attention has been placed on the
placenta and its ability to serve as a conduit for drugs from the mother to the
fetus and vice versa. The ability of the placenta to metabolize many
endogenous and exogenous substances adds a level of complexity to the
understanding of the mechanism behind drug transfer and, ultimately, the
impact on the developing fetus. There are several important experimental
techniques utilized by researchers in an effort to decrease the knowledge gaps
using in vitro experiments performed on the human placenta. These techniques
aim to overcome the ethical and logistic challenges when dealing with human
clinical trials.
IN VITRO STUDIES
Cell and Tissue Culture
With the use of this technique, researchers attempt to delineate the details of
the placenta to better understand the interaction of cells and their phenotypes.
Primary undifferentiated cytotrophoblast cells can be isolated from the term
placenta,
220
then supported to differentiate into a syncytiotrophoblast. The
cells will form a monolayer on semipermeable support and thus can be
beneficial to study the transfer of molecules across its membrane and cellular
metabolism.
221
A disadvantage of this model is the loss of tight junctions when
growing on semipermeable support. Alternatively, another method of cell
culture, as described by Hemmings et al.,
222
solves this problem by forming
confluent monolayers, including the human BeWo, JEG-3, and Jar cell
lines.
165,223,224
Ex vivo Placental Perfusion
This method was first described by Panigel in 1967, then later adapted and
improved.
98,225,226
The advantage of this method is that it provides the closest
model to an in vivo study, making it an ideal model to study drug transfer
across the placenta. Several other functions can be elucidated from this
experiment, including the production of endogenous substances and the effect
of drugs on vascular resistance.66 The placental circulation is reestablished by
running a physiologic perfusate through the maternal and fetal blood vessels in
the placenta in a closed (recirculating) or open (single-pass or
nonrecirculating) circuit (Fig. 9.2). The advantage of the former is that it
allows studying the transfer of drugs and the production of metabolites,
whereas the latter is useful for studying fetal–maternal clearance.
165
One
limitation of this study is the need to use a placenta after a cesarean or vaginal
delivery at term gestation, thus limiting generalizability to earlier in the
pregnancy.
165
However, its importance remains unchallenged, as a recent
review showed that 26 drugs had comparable results in the placenta perfusion
studies and in vivo studies.
227
Figure 9.2 provides an illustration of the setup
of the ex vivo perfusion experiment.
Figure 9.2 Experimental setup for perfusing a human placental lobule ex vitro.
Placenta-on-a-chip Model
Recently, researchers were able to create a device that recapitulates the
placental barrier in an attempt to further our understanding on transport
mechanism.
228
This innovative work entails growing a trophoblast and
endothelial cell population and depicting the specific architecture of the
membrane with careful evaluation of cell–cell junctions and expression of
various active transports, including the BRCP.
228,229
The drug glyburide was
tested in one model which showed an active transport from fetal to mother
circulation, recapitulating that the placenta transport mechanism limits fetal
exposure to glyburide taken by the mother for gestational diabetes.
229
This
promising technology can serve as a reproductive model that will highlight the
transport mechanism and may explain several key links between a drug and its
toxicity in fetal exposure.
IN VIVO STUDIES
The difficulty of incorporating pregnant women in pharmacology clinical
trials is often related to primarily logistical challenges and at times ethical
concerns when dealing with unknown exposures to the fetus that are difficult
to study in utero.
230
The only available study methodology of placental transfer
measures drug levels in the mother and cord blood of the fetus after drug
administration to the mother. This provides very little information on kinetics
and the mechanism behind the transfer. However, the importance of this
method is by obtaining the fetal-to-maternal concentration ratio, which can be
utilized to guide therapy. Ceftriaxone has a high fetal-to-maternal
concentration ratio, making it an ideal drug for the treatment of
chorioamnionitis where you need the antibiotic to accumulate in both the
mother and the fetus who are at risk of complications.
231
However, if therapy
is needed for the mother, it is better only to use a drug with a low fetal-tomaternal ratio such as cyclosporine in patients with a liver transplant.
232
Concerns of confounding the maternal concentration of drugs due to surgery,
anesthesia, or the physiologic changes in pregnancy should be taken into
consideration. Researches have also been looking for other tools such as
biomarkers found in hair and meconium to assess long-term exposure of drugs
in the fetus, particularly intrauterine exposure to drug of abuse.
233
Table 9.3
presents some important drugs that can cross the placenta with their fetal-tomaternal ratio obtained from in vivo studies.
TABLE 9.3
Examples of In Vitro and In Vivo Transplacental Transfer of Drugs of
Therapeutic Interest
PHYSIOLOGICALLY BASED PHARMACOKINETIC
MODELS
While the ex vivo placental perfusion experiment provides insight into
maternal–fetal transfer in a cotyledon, this information can be leveraged
within a physiologically based pharmacokinetic (PBPK) modeling framework
to simulate and predict pharmacokinetics in the fetus.
PBPK models are compartmental models consisting of a plethora of
differential equations describing the processes of absorption, distribution,
metabolism, and excretion (ADME) of a xenobiotic in the body. Importantly,
these models are mechanistic, that is, the ADME processes are
mathematically described based on the understanding of underlying physical,
chemical, and biologic principles. Put differently, the relationship between the
observed data and the model parameters (and the interplay between model
parameters) is specified in terms of the physical, chemical, and biologic
processes that are thought to have given rise to the observed data. The model
parameters thus have a biologic meaning; model parameterization, that is, the
process of assigning a numerical value to a parameter, can be done based on
experimentally measuring or studying relevant model parameters. In a PBPK
model, tissues and organs are hence compartmentalized with knowledge of
their size and composition and structurally arranged in a parallel circuit to
reflect the circulatory system; drug exchange between these organ
compartments is described through the blood flow.
280
Of note, PBPK models
are rarely purely mechanistic, but may contain empirical components; yet,
major parts of the model follow mechanistic principles. Mechanistic models
are especially powerful in that they are more likely to work correctly under
perturbation of the underlying system, meaning that they can be used to predict
the expected outcome in a new scenario.
281
More specifically, PBPK models
have been successfully used to predict drug pharmacokinetics in special
populations, such as preterm neonates,
282
children,
283
and pregnant women.
284
As previously demonstrated by various groups,
285,286
the experimental
results obtained from the ex vivo placental perfusion experiment can be
harnessed in PBPK models. Specifically, these groups used a compartmental
model to first describe the drug transfer in the ex vivo experiment by fitting
unknown parameters (e.g., the transfer clearance, partition coefficient,
potentially elimination rate constants) to the observed data. Thereafter, the