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Owusu Obeng et al. J Transl Genet Genom 2021;5:64-79 I http://dx.doi.org/10.20517/jtgg.2020.52 Page 75

Organ transplant patients
In cases of stem cell, liver, and bowel transplant, special consideration should be taken when collecting and
interpreting pharmacogenetic results. Clinicians must ensure that samples from stem cell transplant patients
are collected prior to the transplant for DNA analysis. This guarantees that the transplant recipient’s DNA
is analyzed and not that of the transplant donor. Moreover, the liver and intestines possess CYP3A enzymes
important for metabolism of many medications including tacrolimus. In addition, preliminary studies have
found that formulation and route of tacrolimus influences the significance of CYP3A5 pharmacogenetic
results [73,74] . When evaluating pharmacogenetic results for liver and bowel transplant recipients; clinicians
should be aware that the genetic makeup of the new graft (i.e., donor’s genotype) may be different from that
of the transplant recipient. Hence, the use of only the recipient’s genetic information may be misleading.
Studies are underway to help unravel the pharmacogenetic complexities related to the type of transplant
and the influence of the recipient versus the donor’s genotypes as it relates to the timing of the transplant
surgery and beyond.

Ontogeny
Neonatal and pediatric patients undergo age related development of metabolizing enzymes. For this reason,
a general knowledge of the enzymes’ maturation process is discussed here. A simplified categorization of
[75]
the process of maturation can be grouped into three categories . The first are enzymes that are expressed
at high levels during gestation and within 1-2 years after birth with CYP3A7 being an example of this
category. The second category comprises CYP3A5 and CYP2C19 which are expressed at constant levels
during gestation. Unlike CYP3A5, CYP2C19’s expression increases throughout the first year of life. The
third category are those enzymes that are not expressed or are at low levels during gestation and increase
substantially during the first to second years of birth. Examples are CYP3A4, CYP2C9, CYP2D6, and
CYP2E1 [62,75] . In general, ontogeny needs to be considered during evaluation of pharmacogenetic results for
neonates, infants, and younger pediatric patients.

Pregnancy
Pregnancy results in a multitude of endocrine as well as metabolic changes that affect interpretation
of pharmacogenetic results. Most CYP450 enzymes are induced during pregnancy namely CYP2A6,
[76]
CYP2B6, CYP2C8, CYP2C9, CYP2E1, CYP3A4, and CYP3A5 . CYP2D6 enzyme levels are induced to
higher levels in the second through third trimester for ultrarapid and normal metabolizers compared
to first trimester [77,78] . Clinically, this indicates that normal metabolizers of these enzymes would need
monitoring for the duration of the pregnancy to ensure efficacy with active drugs such as antidepressants
and antiemetics, and safety with prodrugs such as codeine, since pregnancy may induce CYP2D6,
leading to a potential change in metabolizer status, affecting medications that are metabolized through
CYP2D6 [57,79,60] . However, for pregnant women who are ultrarapid metabolizers, no further adjustments to
the actionable pharmacogenetic recommendations would be anticipated. For instance, ondansetron would
not be recommended for any CYP2D6 ultra-rapid metabolizer regardless of pregnancy status [77-79] . CYP2D6
intermediate and poor metabolizers need no additional adjustments from guideline recommendations
during pregnancy [77,78] . Alternatively, inhibitory effects on CYP1A2 and CYP2C19 enzyme levels have also
been reported during pregnancy [77,80] . Use of caffeine (a substrate of CYP1A2) in the third trimester results
in a 65% decreased metabolism as compared to non-pregnant women . The current limited evidence
[77]
in pregnant women suggest that it is advisable to monitor normal metabolizers in addition to other
actionable phenotypes to ensure that all clinically-relevant factors are carefully considered when utilizing
pharmacogenetic results to make therapeutic decisions in pregnancy.

CONCLUSION
In summary, pharmacogenetic testing is a valuable tool that should be adopted into routine clinical
practice. We provide a review of the preparatory steps necessary to implement a clinical pharmacogenetic