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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5195_Библиотеки_им_академика_М_И_Перельмана.pdf
occurs most commonly as four (*V4) or five (*V5) repeats, and the *V4/*V5
diplotype has been associated with higher erythrocyte TPMT activity compared
to *V4/*V4 or *V5/*V5 diplotypes in one study,
176
and *V6 was associated with
decreased levels of TPMT in another study.
179
In childhood ALL patients,
TPMT expression has been observed to increase 1.5- to 7.9-fold during the
maintenance phase relative to the beginning of treatment, with VNTR*5a/*5a
carriers having the highest levels of TPMT expression during maintenance
treatment, even though they exhibited low expression prior to treatment. In
contrast, carriers of the VNTR*7a allele had the lowest level of enzyme
expression prior to treatment and the lowest increase in activity during the
maintenance phase.
180
Thus, the VNTR polymorphism in the regulatory region of
the TPMT gene affects the level of gene expression, whereas allelic variation in
the coding region of the TPMT gene primarily affects the catalytic activity of the
expressed enzyme.
The small percentage of patients with low to absent TPMT activity is at
increased risk for developing severe myelosuppression if treated with routine
doses of thiopurines, and the most recent CPIC guideline recommends a 10-fold
reduction of dose and reduced frequency from daily to three times per week to
minimize the risk of toxicity; CPIC also recommends decreases in dosing and
adjustment based on the degree of myelosuppression for TPMT intermediate
metabolizers as well.
172
Furthermore, poor metabolizers may be at increased
risk of relapse consequent to inadequate or absent treatment with the
thiopurines. In the context of the expanding use of 6-mercaptopurine and
azathioprine in pediatrics to treat inflammatory bowel disease and juvenile
arthritis and to prevent renal allograft rejection, TPMT deficiency is not a
trivial matter, and risk-to-benefit considerations will differ compared to ALL.
The 2019 thiopurine pharmacogenomics-based dosing guidelines have also
incorporated NUDT15 polymorphisms alongside TPMT.
172
Nudix hydrolase 15,
the protein product of NUDT15, acts as a nucleoside diphosphatase capable of
transforming genotoxic thioguanine triphosphate compounds into less toxic
monophosphates. Among the identified genetic variants, the NUDT15*2 and
NUDT15*3 alleles are currently the most understood with regard to functional
impact. Patients who possess two copies of these alleles or one of each are
considered poor metabolizers, while those with one copy of *2 or *3 and a
function allele (e.g., *1) are classified as intermediate metabolizers.
Deficiencies in both pathways should be considered for thiopurine dosing. For
instance, the likelihood of requiring a dosing adjustment would be expected to
be greater in a TPMT intermediate metabolizer who is also a nudix hydrolase
15 intermediate metabolizer when compared to an individual with solely a
TPMT intermediate-metabolizer status.
172
An association between TPMT deficiencies and cisplatin-mediated toxicity
in cancer patients has been reported, with children apparently at a
disproportionate risk of developing hearing loss after taking cisplatin.
181
This
finding has been replicated by some investigators,
182
but not others,
183
and
remains controversial.
184,185
Carboxylesterases
The observation that heritable butyrylcholinesterase deficiency resulted in
prolonged paralysis following succinylcholine administration was one of the
foundational discoveries in the field of pharmacogenetics. Since then, our
understanding of the role of esterases in metabolism and bioactivation of drugs
and prodrugs has greatly expanded. While multiple esterases are now
recognized to affect the disposition of drugs, attention has been directed toward
carboxylesterases 1 (CES1) and 2 (CES2) in particular. CES1 and CES2 are
part of a broader family of esterases and are responsible for the cleavage of
carboxylic esters into an alcohol and a carboxylate moiety. While there exists
extensive substrate overlap between the two isoforms, CES1 preferentially
hydrolyzes esters with relatively small alcohol substituents and larger acyl
substituent, while CES2 generally favors the reverse.
186
In humans, CES2 is
extensively present in both the liver and the intestine, while CES1 is
preferentially expressed in the liver.
186
Expression of both CES1 and CES2
increases fivefold and threefold, respectively, in the liver from birth to
adulthood.
187,188
While genetic polymorphisms have been identified for both
carboxylesterases, there is currently more evidence supporting the clinical
importance of CES1 genetics. It has been observed that children with a reduced
function polymorphism resulting in an amino acid substitution from glycine to
glutamic acid at position 143 in the CES1 protein require a higher dose of
methylphenidate than those with the wild-type allele.
189
Increased exposure to
the active metabolite of clopidogrel, which is cleared by CES1, and subsequent
clinical responsiveness, has also been observed in adults with this variant.
190
The underlying mechanism of these associations was elucidated by independent
observations of substantially reduced catalytic activity in the CES1 protein
product of this genetic polymorphism.
191
It is worth noting that genetic
polymorphisms in CES1 have also been associated with alterations in the
biotransformation of oseltamivir, a drug frequently reserved for use in infants
and other populations at high risk for influenza-related complications.
192,193
DRUG TRANSPORTERS AND LOCAL DRUG
CONCENTRATIONS
While somewhat overshadowed by the abundance of information on the
pharmacogenomics of drug-metabolizing enzymes, there exists a number of
convincing examples of the importance of transporter pharmacogenomics in
drug action and disposition. Some transporters represent direct targets for
therapeutic agents. Examples include the sodium glucose transporter 2
inhibitors used in the treatment of diabetes and ivacaftor for cystic fibrosis.
When a transporter is a direct target of pharmacologic action, polymorphisms in
the genes encoding for the transporter can play a role in determining the
presence or magnitude of drug response. A particularly relevant example for
pediatrics involves the treatment of cystic fibrosis with ivacaftor. Ivacaftor is a
potentiator of cystic fibrosis transmembrane conductance regulator (CFTR), an
ATP-binding cassette (ABC) transporter, and chloride channel that is defective
in individuals with cystic fibrosis. Only certain mutations that impair CFTR
function will respond to potentiation via ivacaftor. As such, the CPIC guidelines
for ivacaftor state that a patient should be genotyped as positive for the G551D
mutation in CFTR in order to receive the drug.
194
While examples of genotypedependent requirements for pharmacologic action are especially compelling in
making a case for the utility of transporter pharmacogenetics, most of the known
instances where transporter pharmacogenetics influences drug therapy relate to
their role in modulating systemic pharmacokinetics. Over the past two decades,
research in the field of drug transporters has expanded to also include an
equally important emphasis on their role in modulating local drug
concentrations at intracellular sites of metabolic clearance, toxicity, and
therapeutic action. This effect is most pronounced in the case of active
transporters (i.e., those directly or indirectly dependent upon cellular energy
sources to function), which can operate against drug concentration gradients and
are, therefore, capable of maintaining intracellular drug concentrations that are
many-fold greater or less than those of the surrounding extracellular
environment. In their role in modulating local concentrations, a useful functional
classification for discussing drug transporters is to divide them into uptake
transporters, those that bring drug molecules into cells, and efflux transporters,
those that remove drug molecules from cells. Uptake transporters are typically
members of the solute carrier (SLC) superfamily, but members of ABC
transporter family also mediate the active cellular uptake of drugs.
Organic Anion Transporter Polypeptides
Organic anion–transporting polypeptides (OATPs) are a subfamily of SLC
uptake transporters, and four OATP transporters, OATP1A2, OATP1B1,
OATP1B3, and OATP2B1, are widely recognized for their importance in drug
disposition. Targeted proteomics and more traditional immunoblot-based
methods have revealed that OATPs are expressed in a diversity of tissues, with
OATP1A2 and OATP2B1 being almost ubiquitously expressed.
195
By
comparison, OATP1B1 and OATP1B3 protein expression is largely restricted
to the liver.
196–198
According to recent studies utilizing targeted proteomics,
hepatic OATP1B3 expression is present at birth and increases as a child
approaches adulthood, whereas OATP1B1 and OATP2B1 expression remains
relatively unchanged.
199
It is worth noting that prior studies relying upon
Western Blot, real-time PCR (for mRNA), and transporter activity assays in
primary hepatocytes suggest differing maturation profile, and further
confirmatory studies are warranted.
OATP1B1 has a particularly well-defined role in modulating the
pharmacokinetics of statins and other substrates. A considerable amount of
attention has been paid to assessing the impact of genetic polymorphisms in
SLCO1B1, the gene encoding OATP1B1, on statin pharmacotherapy. In
particular, the 521T>C SNP resulting in a change from valine to an alanine at
residue 174 has repeatedly been associated with greater plasma concentrations
and increased risk of myopathies in individuals taking statins.
200–204
Based on
this and other SLCO1B1 polymorphisms, over 30 haplotypes have been
assigned. Alterations in in vivo drug disposition or response have been
observed for several haplotypes, including *1B, *5, *14, *15, *17, and
*27.
205,206
Interestingly, while most of the variant SLCO1B1 haplotypes are
associated with reductions in OATP1B1-mediated transport, the *14 haplotype
was found to be associated with increased OATP1B1 protein expression in the
liver.
207
Not all statins are affected to the same extent by SLCO1B1 haplotypes,
and of the currently marketed statins, simvastatin acid is most affected.
208–211
Current CPIC guidelines recommend the carriers of the *5, *15, or *17
haplotype receive a reduced dose of simvastatin acid or an alternate HMG-CoA
reductase inhibitor.
212
Generally speaking, genotype–phenotype associations for
SLCO1B1*5 and systemic exposure of simvastatin acid and pravastatin are
similar between children/adolescents and adults,
204,213
but interindividual
variability within a genotype group is greater than the difference between
genotype groups, indicating that additional nongenetic factors are also
important.
Organic Cation Transporters
Organic cation transporters (OCTs) are a group of uptake transporters within
subfamily 22 of the SLC family (i.e., SLC22A). OCTs have been implicated in
the modulation of the pharmacokinetics and pharmacodynamics of cationic
drugs, such as cisplatin, citalopram, lamivudine, metformin, morphine,
ondansetron, and sumatriptan. Some drugs are transported preferentially by
certain OCTs, but there exists considerable substrate overlap among isoforms.
Whereas OCT1 and OCT2 are enriched in the liver and kidney proximal tubule,
respectively, OCT3 is expressed more ubiquitously across tissues.
195
Genetic
polymorphisms have been identified in SLC22A1, SLC22A2, and SLC22A3, the
genes encoding for OCT1, OCT2, and OCT3, respectively.
Six haplotypes (*1 through *6) have been described for SLC22A1 based on
the five reduced function polymorphisms (262T>C, 286C>T, 1306G>A,
1365GAT>del, and 1498G>C), and their impact on pharmacokinetics has been
evaluated. Reduced clearance of morphine was observed in children who carry
two reduced function variants (*2, *3, *4, or *5); the *6 haplotype was not
evaluated.
214
A subsequent study in neonates demonstrated similar findings
relating to the *2 through *5 haplotypes and additionally observed reduced
morphine clearance with the *6 variant.
215
The *3 through *6 variants, but not
*2, have also been associated with decreased clearance of fenoterol and
sumatriptan in adults.
216,217
For SLC22A1 polymorphisms, associations between
the decreased function haplotypes and alterations in pharmacokinetics have
been attributed to impaired OCT1-mediated uptake into the liver, the principle
organ of elimination for most of the implicated drugs. However, in addition to
the liver, OCT1 is also present in the intestinal epithelia, and the potential for
OCT1 polymorphisms to alter oral bioavailability and absorption rate should
also be considered.
196
Because the intestine and liver are the sites of pharmacologic effects for
many drugs, impairments in OCT1 function have the potential to alter the
apparent pharmacodynamics of substrates. Associations have been observed
between SLC22A1 polymorphisms and reduced tolerability to metformin, an
OCT1 substrate with adherence issues related to gastrointestinal irritation.
218
Considering the liver is a major site where metformin exerts its therapeutic
effects, it has also been suggested that reduced hepatic uptake, secondary to
SLC22A1 polymorphisms, may result in relatively reduced glycemic control.
However, experimental results investigating this hypothesis have been
inconsistent.
219
Variants of the gene encoding OCT2 (i.e., SLC22A2) that may be
relevant in metformin therapy have also been identified. In particular, the
nonsynonymous 808G>T polymorphism results in a reduced function allele and
has been associated with impaired renal tubular secretion of metformin.
220,221
Reduced incidence of nephrotoxicity to cisplatin, another substrate of renal
OCT2, has also been in observed in carriers of the 808G>T SNP.
222
While
variants of SLC22A3 (i.e., OCT3) have been identified, their capacity to impact
drug disposition and response remains relatively unclear.
Breast Cancer Resistance Protein
Breast cancer resistance protein (BCRP) is a member of the ABC family of
active transporters. It is encoded by the ABCG2 gene and is expressed in many
epithelial and endothelial cells in humans. Oriented outwardly, BCRP
transports substrates out of cells and contributes to the critical restrictive
functions of the testis, placenta, and the blood–brain barrier (BBB). In the liver,
BCRP is expressed on the canalicular membrane of hepatocytes and contributes
to the biliary secretion of drugs, such as nitrofurantoin and rosuvastatin.
223
Targeted proteomic studies have revealed that BCRP expression in the liver is
relatively stable from birth to adulthood and that age may not be a substantial
independent source of interindividual variability.
199
Most of the genetic polymorphisms in ABCG2 for which a functional impact
has been established are rare, with the notable exception of 421G>T, a
particularly common SNP among individuals of Han Chinese ancestry.
224
The
421G>T SNP results in a reduced function allele and has been associated with
increased exposure to rosuvastatin and greater reductions in low-density
lipoprotein (LDL) cholesterol.
202,225–227
This association presumably is a
consequence of impaired secretion of rosuvastatin into the bile via hepatic
BCRP. Conversely, it has been observed that patients with the relatively
reduced function GT or TT genotypes appear to have reduced effectiveness of
allopurinol in gout.
228,229
However, a mechanism has yet to be established, and
the association may be the result of the 421G>T SNP being in linkage
disequilibrium with another genetic polymorphism.
Whereas rosuvastatin and allopurinol provide the most convincing examples
of a role for the clinical utility of BCRP pharmacogenetics, they are not
frequently used drugs in the pediatric population, and studies specifically
investigating the impact of BCRP genetic polymorphisms on drug exposure and
response in children have been limited. Clearance and incidence of adverse
events in children receiving tacrolimus for hematopoietic stem cell transplants
have been observed to be unaffected by the 421G>T variant.
230
In a study of
methotrexate pharmacokinetics in a pediatric population, another relatively
more common BCRP SNP, -24C>T, was not found to have a detectable effect.
231
Other pediatric-relevant drugs, such as lamotrigine and sulfasalazine, have been
identified as BCRP substrates, and although clinical studies in adults suggest a
potential effect of the 421G>T SNP on their pharmacokinetics, no pediatric data
are currently available.
232–234
Multidrug Resistance–Associated Proteins
The multidrug resistance–associated protein (MRP) transporters are a
subfamily of ABC efflux transporters with an affinity for organic anionic
compounds. A variety of drugs and endogenous substrates, such as bile acids,
are transported by MRPs. Broadly speaking, MRPs have an affinity for
conjugated compounds, including phase II drug metabolites (e.g., glucuronide,
glutathione, and sulfate conjugates). In humans, MRPs are expressed in all
tissues traditionally considered important in governing pharmacokinetics. In the
small intestine, MRP2, and, possibly, MRP4 are localized to the apical
membrane of the enterocytes, whereas MRP1, MRP3, and MRP5 are expressed
on the basolateral membranes.
235
In the liver, MRP2 is present in the bile
canalicular membrane, and MRP1, MRP3, MRP4, and MRP5 are expressed in
the sinusoidal membranes of the hepatocytes.
235
In the kidney, MRP2 and MRP4
are found on the apical membranes of the proximal tubule epithelial cells,
whereas MRP1 and MRP3 are expressed in the basolateral membranes.
235
In the
BBB, MRP1, MRP4, and MRP5 are expressed along the luminal membranes of
the capillary endothelial cells, thereby restricting access of substrates to the
cerebrospinal fluid.
235
Broadly speaking, MRPs are oriented outwardly, and
their action results in reduced intracellular concentrations of their respective
substrates.
MRP1 is encoded by the ABCC1 gene and is perhaps the most studied MRP
transporter regarding protein structure–function relationships. It has an affinity
for transporting phase II drug metabolites (e.g., glucuronide and glutathione
conjugates), anthracyclines, and vincristine. Much of the focus of ABCC1
pharmacogenetic studies in children has related to the effect of allelic variation
on adverse drug reactions to anticancer agents. For the most part, no
associations of clinical consequence have been found in pediatric trials.
Notably, the intronic 825T>C SNP, present in approximately 10% of the African
populations, was associated with incidence of anthracycline-induced
cardiotoxicity in children.
236
However, a follow-up study could not confirm the
association.
237
MRP2 shares a high degree of substrate overlap with MRP1. In humans,
MRP2 is extensively expressed in the apical brush border of the kidney
proximal tubule. In conjunction with other transporters, including MRP4, it
plays an important role in secreting substrates from inside proximal tubule
epithelial cells out into the glomerular ultrafiltrate. A reduced function variant
resulting from the -24C>T SNP in ABCC2, the gene encoding for MRP2, has
been associated with tenofovir-induced nephrotoxicity in adults.
238,239
However,
the mechanism underlying a role of MRP2 genetics is less clear, given that
tenofovir has not been consistently shown to be a substrate of MRP2. In the
pediatric population, the -24C>T SNP has also been associated with elevated
trough concentrations of voriconazole and increased incidence of toxicities to
methotrexate.
231,240
MRP3 has an affinity for phase II drug metabolites, particularly glucuronide
conjugates. In perfused livers isolated from ABCC3 (i.e., MRP3) knockout
mice, secretion of acetaminophen glucuronide into the blood was decreased,
and secretion into the bile was increased.
241
Similar findings have reported for
morphine. In ABCC3 knockout mice, morphine-3-glucuronide concentrations are
increased in the bile, while plasma concentrations are dramatically reduced
(~50-fold).
242
In humans, reduced expression of ABCC3 mRNA has been
observed in individuals who are homozygous for the -211C>T SNP,
243
and the
presence of the T allele also has been associated with reduced systemic
exposure to morphine-glucuronide metabolites in children.
244
MRP4 is predominantly responsible for transporting nucleoside drugs, such
as tenofovir and ganciclovir. Like many other MRPs, it is also capable of
transporting methotrexate and phase II drug metabolites. One of the clearer
examples of an impact of MRP genetics on drug disposition is the 3463T>C
polymorphism in ABCC4, the gene encoding MRP4. The variant is quite
common, occurring in 10% to 20% of individuals, and is associated with
increased plasma and cellular tenofovir exposure and decreased tenofovir renal
clearance in adults.
245,246
Other studies have also connected the relatively
common 4131A>C and 4976A>G SNPs in ABCC4 with increased tenofovir
clearance and incidence of tenofovir-induced nephrotoxicity, respectively.
247,248
MRP5 has a substrate profile that is similar to MRP4, consisting of nucleosides,
nucleotides, and methotrexate. However, relatively less is known about the
pharmacogenetics of ABCC5 (i.e., MRP5), particularly in pediatrics. There is
some evidence suggesting MRP5 may play a role mitigating the severity of 5fluorouracil (5-FU) and irinotecan-induced gastrointestinal toxicity.
249
P-Glycoprotein
P-glycoprotein (P-gp) is an ABC efflux transporter encoded by the ABCB1, also
known as the MDR1, gene. Generally, it transports lipophilic and cationic
compounds and has a high substrate overlap with the drug-metabolizing enzyme
CYP3A. In humans, P-gp is expressed extensively in the intestines, kidneys,
BBB, placenta, and liver.
250
In the small intestine and liver, where CYP3A and
P-gp are co-expressed, evidence suggests the two proteins operate
synergistically.
251
As such, reductions in P-gp function due to factors including
genetic polymorphisms may also reduce the apparent activity of CYP3A. Much
like CYP3A4, hepatic protein expression of P-gp has been shown to increase
from birth to adulthood and that age may be a determinant in the functional
consequences of interplay between the two proteins. Polymorphic expression of
CYP3A5 adds an additional layer of complexity, and CYP3A5 polymorphisms
may represent effect modifiers on associations between ABCB1 polymorphisms
and drug exposure. Enzyme-transporter interplay may even explain the results of
one study where the CC genotype (1236C>T SNP) for ABCB1 was associated
with decreased tacrolimus blood concentrations only in children who also
possessed at least one copy of the active CYP3A5*1 allele.
252
P-gp also plays a critical role in restricting drug transit across the BBB.
Functional impairment of P-gp at the BBB could result in increased efficacy and
toxicity of drugs that exert pharmacologic actions in the central nervous system
(CNS), presumably through reduced efflux from the CNS. With this in mind, it is
interesting to note that 1236C>T has been associated with increased response to
risperidone and combined anesthetic regimens (e.g., remifentanil–sevoflurane
and remifentanil–propofol).
253–255
Both 1236C>T and 3435C>T in ABCB1 have
been found to be associated with increased incidence of methotrexate-induced
toxicities in children,
256
and 3435C>T has also been associated with increased
neuropsychiatric adverse events in children taking oseltamivir.
257
Generally
speaking, efforts to demonstrate a clear relationship between discrete genetic
polymorphisms and transporter function have been complicated by the
tremendous degree of variation in the ABCB1 gene. While some utility has been
found in aggregating multiple polymorphisms into haplotypes, much more work
is needed to clarify P-gp pharmacogenetics.
HYPERSENSITIVITY REACTIONS
Many drugs and their metabolites can bind to proteins in the body and elicit
hypersensitivity reactions. The potential for hypersensitivity reactions is
especially great when drug or drug-modified peptides bind to the major
histocompatibility complex (MHC) proteins that are important in T-cell
recognition of antigens. Genetic variation in the HLA genes that encode MHC
proteins has been shown to be reliable predictors of risk for hypersensitivity
reactions to certain drugs. Hypersensitivity reactions to abacavir commonly
result from the presence of the HLA-B*57:01 allele, which occurs in
approximately 5% of individuals of European ancestry.
258
Prospective screening
for the HLA-B*57:01 allele has dramatically reduced incidence of abacavir-
induced hypersensitivity reactions.
259
The presence of HLA-B*15:02, an allele
that is much more commonly encountered in individuals of Asian ancestry, has
been associated with the incidence of SJS/TEN in children treated with
carbamazepine and oxcarbazepine.
260
The FDA-approved product label
recommends testing for HLA-B*15:02 be conducted for patients with ancestry
in populations with increased frequency of the allele prior to treatment with
carbamazepine and oxcarbazepine.
261,262
While the HLA-B*15:02 allele has also
been associated with severe cutaneous adverse reactions to phenytoin,
pharmacogenetics testing is currently not indicated prior to imitating therapy.
However, alternative medications (other than fosphenytoin, carbamazepine, or
oxcarbazepine) should be considered if a patient is known to carry the HLA-