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Page 74 Owusu Obeng et al. J Transl Genet Genom 2021;5:64-79 I http://dx.doi.org/10.20517/jtgg.2020.52

CYP2D6
For the highly polymorphic CYP2D6 gene, calculation of an activity score is used to translate genetic
[59]
variants to phenotype (e.g., metabolizer status) . The CPIC guidelines have addressed incorporation of
an inhibitor drug when calculating activity scores based on a system used for tamoxifen in breast cancer
patient study [60,61] . Substrates of CYP2D6 include propafenone, paroxetine, risperidone, codeine, tramadol,
[62]
and atomoxetine . When concomitant strong CYP2D6 inhibitors are present, the activity score is
multiplied by zero and the resultant phenotype is a poor metabolizer while for moderate to weak inhibitors
the activity score is halved, and so the implicated phenotype will vary. For example, paroxetine significantly
inhibits flecainide, desipramine, aripiprazole, and R-methadone metabolism in individuals carrying two
functional alleles than those with decreased function alleles . In addition, since herbal supplements
[55]
are also metabolized via the CYP450 enzyme system and can cause phenoconversion, patients should be
cautioned to report all active herbal supplement usage. Supplements such as bush mint, bush tea, or pignut
[52]
should be monitored for their inhibitory effects on CYP1A2, CYP3A4, and especially CYP2D6 .
CYP2C19
The interaction between proton pump inhibitors and clopidogrel is attributed to inhibition of CYP2C19,
however this has not been found to be a class effect by all proton pump inhibitors. Their influence on
clopidogrel bioactivation differs by the agent and by the CYP2C19 metabolizer status of the patient.
Omeprazole, esomeprazole, and rabeprazole demonstrate stronger competitive CYP2C19 inhibition than
lansoprazole and have significant impact in patients who are carriers of functional or increased function
alleles (i.e., CYP2C19 normal, rapid and ultrarapid metabolizers) compared to carriers of loss of function
alleles (i.e., CYP2C19 intermediate and poor metabolizers) [55,63] . A prospective double-blind, cross-
over, randomized study, found that the use of esomeprazole significantly reduced platelet inhibition in
clopidogrel-treated acute coronary syndrome patients who were carriers of *17 or *1/*1 compared with
[64]
those treated with clopidogrel and placebo. This interaction was not observed among *2 carriers .
CYP2C9
Clinically relevant inhibitors of CYP2C9 include amiodarone, fluconazole, and miconazole. Co-
administration of warfarin (CYP2C9 substrate) and amiodarone (CYP2C9 inhibitor) require adjustment of
dose, which is accounted for in warfarin pharmacogenetic dosing algorithms [65,66] . Likewise, fluconazole,
an inhibitor of CYP2C9 among other enzymes, produced a 2-fold increase in siponimod plasma
concentrations among CYP2C9 normal metabolizers. Notably, normal metabolizers of CYP2C9 can be
phenoconverted to intermediate or poor metabolizers [67,68] . Commonly prescribed CYP2C9 substrates
like warfarin, phenytoin, proton pump inhibitors, and non-steroidal ant-inflammatory drugs should be
[62]
monitored for phenoconversion .
Thiopurine Methyltransferase
TPMT activity is important for substrates including mercaptopurine, azathioprine, thioguanine, and
cisplatin [69,70] . This enzyme’s activity is affected by recent blood transfusions for which enzyme activity
testing alone may result in inaccurate results unlike pharmacogenetic testing, which remains stable
[71]
despite transfusion . However, co-administration with additional bone marrow suppressing drugs such
as sulfasalazine, mesalamine, and olsalazine should be carefully monitored and incorporated into the
[54]
interpretation of pharmacogenetic results .

Moreover, social habits should also be taken into consideration. For instance, smoking induces CYP1A2
which may be relevant for drugs affected by CYP1A2 such as caffeine, clozapine, fluvoxamine, olanzapine,
[72]
and theophylline . Phenoconversion is not permanent so once the interacting medication or habit is
discontinued, the pharmacogenetic-guided therapeutic recommendation should be re-examined and
corrected as necessary.