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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
appear to transfer across the placenta readily.
87,88
Similarly, antibiotics such
as ampicillin and methicillin seem to follow the same flow.89 However,
neuromuscular blockade drugs, which are large quaternary ammonium
compounds that are highly ionized at physiologic pH, cannot cross the
placenta.
90
Placental Binding
In vitro studies illustrate how the placenta can serve as a depot for some
drugs, particularly with very lipophilic drugs which can readily cross the
lipid bilayer of the syncytiotrophoblast cell.91 The change in serum protein
concentration has an implication on the drug transfer by affecting its binding to
tissue protein. If the drug binds tissue proteins with a higher affinity than
serum proteins, this allows the drug to be removed from the protein binding in
plasma and cross more readily to the placenta.92 One study was able to show
that the increasing fetal circulation of albumin enhances the uptake of steroids
and freeing them from entrapment by tissue proteins in the placenta.93 The
immunosuppressive drug tacrolimus is used during pregnancy for renal
transplant patients, and it has been shown that it can be entrapped in the
placenta. Clinically, placental insufficiency has been associated with the use
of calcineurin inhibitors of which tacrolimus is an example, and this
entrapment maybe one of the causes.
94,95
Sildenafil, a phosphodiesterase-5
inhibitor given to treat pulmonary hypertension during pregnancy, has also
been shown to accumulate in the placenta.96 Interestingly, the accumulation of
drugs in the placenta can be advantageous, such as the case of treating
placental toxoplasmosis infection with spiramycin, a drug that concentrates in
the placenta to help reduce maternal-to-fetal transmission.97 The importance
of placental perfusion studies that specifically investigate the effect of
maternal and fetal protein concentrations is imperative in understanding yet
another layer of complexity in the transfer of drugs across the placental
barrier.
MECHANISM OF TRANSPORT
Simple Diffusion
Most drugs cross the placenta by simple diffusion, which is a passive process
that is dependent on the concentration gradient of the drug. Antipyrine is a
classic example of this type of transplacental diffusion and is the most
important molecule used in ex vivo perfusion studies because it serves as an
indicator of experimental validity.98 Passive diffusion over a biologic
membrane is typically described by Fick’s first law of diffusion. Assuming a
time-independent linear concentration profile, the diffusion rate of a drug
across the placental membrane can be expressed as follows99:
where Cm and Cf is the concentration of unbound, uncharged drug on the
maternal and fetal side, respectively; D is the drug’s diffusion coefficient; α is
the partition coefficient of the drug into the membrane; SA the surface area of
the cell membrane of exchange; ∆x is the width of the cell membrane; Vm is
the volume of the fluid in which the drug is dissolved on the maternal side
(i.e., the volume of the maternal blood plasma filling the intervillous space);
and P is the drug’s permeability coefficient. Likewise, the equation for the
fetal concentration is as follows:
The rate of diffusion of a drug is directly proportional to the surface area
of exchange (SA) and the concentration gradient across the membrane (Cm–C
f
) and inversely proportional to the thickness of the membrane (∆x). The
thickness and surface area of exchange undergo gestation-specific changes
during pregnancy. Several studies showed that the thickness decreases, while
the surface area increases as pregnancy progress, resulting in an increased
placental transfer during gestation.
100,101
Extrapolating this into in vivo studies
is challenging as the anatomic changes are more complex. Thornburg and
Faber
102
were able to show the importance of the fetal endothelium layer,
which is not much altered during pregnancy, in limited drug diffusion, and is
responsible for the resistance to compounds with large MWs.
100,101
The syncytiotrophoblast barrier is a lipid bilayer that favors molecules
that are of low MW, unionized, and relatively hydrophobic (lipophilic).
82
However, extremely lipophilic drugs can get stuck and become constituents of
the cell membrane (e.g., thyroid hormones) requiring other forms of transfer
across the membrane, such as active transport.
103,104
Measuring lipophilicity
by means of the compound’s partition ratio between octanol and water (log P
value) or aqueous buffer with a pH of 7.4 (log D value) can be used as a first
screening tool to assess whether a given compound is likely to cross the
placenta readily.
105
Also, toxic waste products from the fetus are transferred
across the placenta by simple diffusion, including urea, bilirubin, and carbon
dioxide.
91
Facilitated Transport
This transport mechanism is similar to simple diffusion. It does not require
energy expenditure, and the direction of flow is dependent on the
concentration gradient but differs in that it requires a carrier or transporter.
106
The goal of the transporters is to facilitate the transfer of nonlipid-soluble
compounds down their concentration gradient. Although Fick’s law does not
apply here, this mechanism is under the influence of competitive and
noncompetitive inhibition, stereoselectivity, and saturation kinetics.
107
Maternal disease states such as preeclampsia or elevated steroid levels may
affect transporter function.
108
The most commonly studied transporters of the
placenta belong to the solute carrier family (SLC), which constitutes several
subgroups including organic anion transporters (OATs), organic anion
transporting polypeptides (OATPs), organic cation transporters (OCTs),
organic cation/carnitine transporters (OCTNs), multidrug and toxin extruding
protein 1 (MATE1), and nucleoside transporters (NTs).
106
Ganciclovir is an
antiviral drug that utilizes this mechanism by entering the basolateral side
(maternal) into the syncytiotrophoblast but follows a passive diffusion after
that to reach the fetal circulation.
109
Studies showed the presence of carrier
proteins for cephalexin and glucocorticoids. Other compounds that resemble
endogenous substances are assumed to be transported by this mechanism as
well.
110,111
Organic Anion Transporters
The OAT family includes seven members (OAT1 to OAT7), of which OAT4 is
specific to humans. OAT4 is localized at the basolateral membrane of the
syncytiotrophoblast, in addition to its presence in the kidneys and the liver.
112
Small, amphiphilic organic anions, including antibiotics, angiotensinconverting enzyme inhibitors, diuretics, and nonsteroidal anti-inflammatory
drugs, are known substrates.
113
This transporter also plays an important role in
the placental synthesis of estrogen by transporting C-19 precursor compounds
necessary for the pathway and protect the fetus from toxicity of steroid
sulfates.
114
A study showed that olmesartan undergoes bidirectional transport
at the basolateral membrane.
115
Newly developed anti-HIV and anti-HCV
drugs are anionic compounds and may play part in drug–drug interaction at the
level of this transport.
116
Organic Anion Transporting Polypeptides
The OATP family includes two important membranes in placental transport,
the basolateral OATP2B1 (OATP-B) and the apical OATP4A1 (OATPE).
114,117
The former is involved with OAT4 in the estrogen synthesis in the
placenta in addition to transporting drugs such as pravastatin, fexofenadine
glyburide, methotrexate, imatinib, and repaglinide.
118–122
On the other hand,
OATP-E plays an important physiologic role in transplacental transport of
endogenous substances, particularly thyroid hormones.
117
Organic Cation Transporters
The OCT is a uniporter in which its substrates are hydrophilic, organic
cations and that its transport is electrogenic and dependent on the
electrochemical gradient of the transported substrate.
123
Among the three
OCTs (OCT1 to OCT3), OCT3 is most abundant in the placenta and is located
on the basolateral membrane.
112
The physiologic role of OCT3 is limited to
transfer of catecholamines from the fetal circulation and the release of
acetylcholine from the placenta along with OCT1.
124,125
Metformin is one of
the substrates of OCT3.
126
Organic Cation/Carnitine Transporters
The OCTNs are also members of the same family of OCTs, which is SLC22A,
and have three different transporters OCTN1, OCTN2, and OCTN3. It is
responsible for the influx of carnitine in addition to the cationic molecules and
is localized at the apical membrane.
127
Carnitine is important in oxidation of
fatty acids in the mitochondria of the fetus.
128
OCTN2 is expressed early in
pregnancy and continues to be expressed unchanged till term; however,
carnitine transport can be affected by preeclampsia.
129
Substrates for OCTN1
include quinine, quinidine, and verapamil, whereas OCTN2 involves the
transport of spironolactone, cephaloridine, and valproic acid.
130
OCTN3 is
not well known to be involved in xenobiotic transport and is suggested that its
function is limited to carnitine transport.
112
Multidrug and Toxin Extrusion Proteins
The MATEs are antiporters that utilize the H+ concentration gradient to
transfer molecules across the cell membrane.
131
Characteristically, this class
of transporters is located on the apical side and collaborates with OCTs to
make an efficient transport mechanism that limits fetal exposure to drugs. In
one study, Ahmadimoghaddam et al. have shown that OCT3 transports
cationic compounds from the fetal circulation into the placenta, and the MATE
transporters pump those back to the maternal circulation.
132
There is a wide
variety of substrates that are shared, including many endogenous molecules
(estrogen, progesterone, corticosteroids) and exogenous drugs (acyclovir,
metformin, procainamide, imipramine).
133
Nucleoside Transporters
NTs are bidirectional transporters that are divided into two categories,
equilibrative NTs (ENTs) and concentrative NTs (CNTs), and their function is
uptake of natural nucleoside needed for physiologic processes.
112
Isoforms of
the ENTs, ENT1 and ENT2, are expressed on the apical and basolateral sides
of the syncytiotrophoblast membrane, respectively.
134
They play a role in the
effect of the pharmacokinetics of nucleoside reverse transcriptase inhibitors
(didanosine and zalcitabine), antihepatitis therapy (ribavirin and entecavir),
and antineoplastic drugs (gemcitabine and cladribine).
135–137
Pinocytosis and Endocytosis
This is an endocytosis-driven process, facilitating transfer of large molecules
like (endogenous) immunoglobulins or exogenous monoclonal antibodies.
PEGylation of monoclonal antibodies, such as certolizumab, reduces its
placental transfer.
138
Megalin, a known endocytic receptor, is responsible for
the transfer of aminoglycosides such as gentamicin, which is used for the
treatment of intra-amniotic infections. From a clinical perspective, fetal
exposure to gentamicin is known to result in nephrotoxicity, which is believed
to be mediated by megalin-mediated endocytosis and accumulation of the drug
in fetal renal epithelium.
139,140
Active Transport
Primary active transport is an adenosine triphosphate (ATP)-dependent
process that can primarily work against a concentration gradient, while a
secondary active transport utilizes the energy stored in the electrochemical
gradient of a cotransported ion like Na+, Cl−, and H+.
141
These transporters
play an essential physiologic role in the exchange of nutrients from the mother
to the fetus and waste products from the fetus to the mother. It is believed to
be the mechanism which many amino acids, vitamins, and glucose utilize. It is
also incorporated in the protective role of the placenta by facilitating the
efflux of xenobiotics that might be harmful to the fetus.
66,142–144
Most of the transports belong to the ATP-binding cassette (ABC) protein
family, which contains several subfamilies that have been shown to exist on
both basolateral and apical membranes of the syncytiotrophoblast.
145
Of those,
the most studied in the placenta are P-glycoprotein, multidrug resistanceassociated proteins (MRPs), and breast cancer resistance proteins
(BRCPs).
146,147
Initially, these transporters were identified in cancer patients
resistant to chemotherapy; more studies have been shown that these
transporters are found in the placenta and that drug interaction with these
transporters is implicated in controlling several factors of pharmacokinetics,
including absorption, distribution, and elimination.
146
Some other transporters
have also been described and are present in the placenta, including OCTs,
serotonin transporter, norepinephrine transporter, sodium/multivitamin
transporters, and monocarboxylate and dicarboxylate transporters.
Knowledge of their role in modulating drug transport across the placenta and
fetal pharmacology is limited. Figure 9.1 illustrates the distribution of the
transporters across the basolateral and apical sides of the placental interface.
P-glycoprotein (MDR1)
The P-glycoprotein, or “permeability” protein, was first discovered in 1976
in an ovarian cell.
148
It is encoded by the ABCB1 (MDR1) gene in humans and
serves to protect cells and tissues from harmful xenobiotics.
149
Pglycoproteins are mainly found on the apical side facing the maternal
circulation in the placental syncytiotrophoblast, and its physiologic function is
the transfer of hydrophobic cationic compounds from the fetus to the maternal
circulation.
150
Their expression is higher during the first trimester and
decreases at term,
151,152
and in the placenta than in the liver.
153
The implications of P-glycoprotein in the placenta are evident from the
transfer of vincristine, vinblastine, and digoxin into the trophoblast cells
showing preferential uptake in the fetal-to-maternal direction
154
and from an in
vitro study showing trophoblasts pumping cyclosporin out of the cells.
155
Substrates for this enzyme are not structurally related; they include a wide
array of drugs, such as cardiovascular (digoxin, statins), HIV protease
inhibitors (tenofovir disoproxil fumarate, saquinavir), anticancer drugs
(paclitaxel), cyclosporin, and others.
57,147,156
Also, some drugs may serve as
inhibitors, including cyclosporin and verapamil. As such, their intake might
affect the exposure of the fetus to toxic compounds.
157
One example of this
inhibition can be illustrated in the antenatal therapy of fetal supraventricular
tachycardia using digoxin for the mother. When treatment with digoxin as
monotherapy fails, verapamil is usually added. Since digoxin is a good
substrate to P-glycoprotein, the addition of verapamil is thought to increase
fetal exposure to digoxin by inhibiting the P-glycoprotein.
66,154
Clinically, the understanding of how P-glycoprotein works at the level of
syncytiotrophoblast membrane can lead to potential advances in
pharmacotherapy during pregnancy. In case of HIV transmission, the current
regimen involves zidovudine, which has been shown to cross the placenta and
accumulate in the fetal circulation to ensure the protection of the fetus.
However, protease inhibitors, which have been an essential component of
highly active antiretroviral therapy (HAART) for HIV patients, cannot cross
the placenta readily because of several factors, including the effect of the
efflux transporter P-glycoprotein, and thus limiting its clinical effectiveness.
In the future, it may prove beneficial to administer an inhibitor of the
transporter in conjunction with a protease inhibitor to achieve adequate levels
of the latter in the fetal circulation.
158
The efficacy of glucocorticoids in lung maturation has been proven to be a
critical measure in reducing respiratory distress syndrome in preterm babies,
among other important reductions in neonatal morbidity.
159
Antenatal
glucocorticoid, being a substrate of P-glycoprotein, can cross the placenta
rapidly via passive diffusion to reach fetal circulation aided by the
concentration gradient. P-glycoprotein may play a role in the development of
this gradient by pumping glucocorticoid from the fetus into the maternal
circulation.
160
Furthermore, several antidepressants have been substrates for Pglycoprotein, and studies showed umbilical cord concentration is lower than
the maternal concentration, thus highlighting yet another benefit of Pglycoprotein in reducing exposure of antidepressants to the fetus.
147,161
Thus,
drug–drug interaction and drug–transporter interaction are both crucial
parameters to be explored in order to improve drug choice in pregnancy.
Methadone is also another known drug to be transported by the Pglycoprotein across the placenta in which the activity and expression affect
the fetal concentration.
162
Genetic variation in transport gene expression
results in variability of fetal drug exposure.
163
The clinical picture of neonatal
abstinence syndrome depends on the understanding of how the placenta
regulates the pharmacokinetics and pharmacodynamics of opiates crossing
and that is one contributor to its complexity, as several other variables such as
polypharmacy, dosage, or use of alcohol and smoking also contribute.
163
Multidrug Resistance Proteins
The MRP family belongs to the ABC protein family of transporters that plays
an essential role in regulating the active transport of substrates in the placenta,
specifically the unconjugated, amphiphilic anions and conjugated lipophilic
compounds (glutathione, glucuronate, and sulfate).
164
There are several
members of this family, of which MRP3 is the most expressed in the placenta
and plays an essential role in the transport of drugs from the fetal to the
maternal side. Other MRPs can be found on the apical membrane, basolateral
membrane, and/or on fetal endothelial cells.
165
Apical and basolateral
localization of MRPs may indicate their role in placental transport from
fetuses to the mother and from mother to fetus, respectively.
166
The
physiologic role of the MRPs is limited to the removal of waste products and
bilirubin from the fetus to the mother.
124,157
Several drugs serve as substrates
for this active transporter, including anticancer agents (methotrexate,
etoposide, vinca alkaloids, platinum-based compounds), HIV protease
inhibitors, acetaminophen, and antibacterial agents (grepafloxacin and
ampicillin).
66,167
Breast Cancer Resistance Proteins
This ATP-dependent transport is present on the apical side of the
syncytiotrophoblast and the fetal endothelial cells since the first trimester;
thus, it has a role in the efflux of many endogenous and exogenous
compounds.
165
Among all tissues, the expression of BRCP is highest in the
placenta, making it an exciting target for research to elucidate its function in
the maternal–fetal interface.
150
Although its physiologic function remains
ambiguous, it plays a vital role in the efflux transport of anticancer drugs
(methotrexate, doxorubicin, daunorubicin, mitoxantrone, topotecan,
irinotecan), antiretroviral (zidovudine, lamivudine), glyburide, nitrofurantoin,
cimetidine, and several others.
17,112,165,168
Interestingly, glyburide, a prominent
oral antidiabetic medication that has been suggested for the treatment of
gestational diabetes in the mother, was less popular among physicians due to
the side effects in the neonate, including hypoglycemia. However, studies
have shown that there is little transfer of glyburide across the placenta and
that the fetal concentration in treated women is minimal, suggesting a more
complex interplay between different efflux transporters and their expression
in the membrane of the syncytiotrophoblast.
169
PLACENTAL METABOLISM
One of the placenta’s critical roles, which may be of concern in
pharmacotherapy, is the ability to process endogenous and exogenous
compounds into their metabolites through phase I and phase II
biotransformation. This function of the placenta has not been well studied, and
its importance is yet limited. The enzymes responsible are mainly localized in
the endoplasmic reticulum and mitochondrial membrane of the
syncytiotrophoblast, and their expression varies by gestational age, where the
maximal expression is often believed to be in the first trimester.
170–172
PHASE I BIOTRANSFORMATION
The placenta utilizes a myriad of enzymes from the cytochrome P450 (CYP)
system that has been extensively studied in the liver. The most commonly
expressed enzyme is CYP19, which is responsible for metabolizing many of
the xenobiotics that cross the placenta, in addition to its physiologic role.
173
Other enzymes commonly expressed include members of CYP1, CYP2, and
CYP3 enzymes. CYP2 and CYP3 enzymes have not been well studied as their
expression in the placenta is relatively unnoticeable.
Cytochrome P450 CYP19 Family
CYP19 enzymes, also known as the aromatase enzymes, play an important
role in steroid synthesis, particularly of estrogen necessary for the
maintenance of pregnancy.
174–176
It is responsible for the metabolism of
buprenorphine into norbuprenorphine, an alternative drug to methadone in
treating opiate abuse patients. Of clinical relevance, both drugs have been
prescribed during pregnancy and have been linked to neonatal abstinence
syndrome, even though risk was minimal in the buprenorphine therapy.
177–180
It
has been shown that both methadone and buprenorphine may affect the
physiologic function of CYP19 in estrogen biosynthesis.
181
CYP19 has been
shown to metabolize glyburide.
182
The metabolite generated can cross into the
fetal tissue in in vitro studies. It is yet unclear whether this metabolism holds
true in vivo and the extent of its effect on the imbalance of the fetal
euglycemia state.
183
Cytochrome P450 CYP1 Family
CYP1 enzymes, including CYP1A1, CYP1B1, and CYP1A2, are expressed in
the placenta of women who have been smoking during pregnancy, particularly
the form CYP1A1. On the other hand, CYP1A2 is mainly expressed in the
liver.
184,185
Physiologically, these are involved in the biosynthesis of steroids
such as estradiol. CYP1B1 plays a role in the metabolism of testosterone and
progesterone and also in retinoic acid, an essential compound in the formation
of the eye.
186–189
Clinically, CYP1B1 mutation has been linked to primary
congenital glaucoma as the enzyme is known to metabolize retinoic acid.
190
However, the involvement of CYP1B1 in the biotransformation of drugs is
relatively minimal.
171
Smoking has been shown to play a role in regulating