Page 18 - Read Online

Page 268 Arroyo Seguí et al. J Transl Genet Genom 2020;4:263-77 I http://dx.doi.org/10.20517/jtgg.2020.35

PHARMACOGENES: DOPAMINERGIC SYSTEM
As discussed, buprenorphine acts on κ-receptors via antagonism. These receptors are expressed in
[40]
dopaminergic neurons, where they modulate the release of dopamine . The dopaminergic system has
[56]
been tied to signaling pathways related to reward, mood, and behavior . κ-Receptor agonists inhibit the
release of dopamine, which can induce stress and dysphoria . Furthermore, substance-dependent states
[57]
are associated with κ-opioid system overdrive, which may reinforce drug-seeking behaviors due to the
high levels of stress. Buprenorphine administration may antagonize these receptors, helping to normalize
levels of dopamine in the nucleus accumbens, and potentially improving mood and impulsive behavior
tendencies. Other monoamines (e.g., serotonin) may also be involved in these antidepressant effects. To
date, several studies have evaluated the relationship between dopaminergic pharmacogenes and the clinical
outcomes of buprenorphine therapy.

D2-receptor gene (DRD2) dysfunction has been related to drug-seeking behavior, and therefore, genetic
[58]
variants may influence OUD treatment response . Although the DRD2 TaqI A1 polymorphism has been
associated with poor outcomes among methadone patients, no such association has yet been observed with
[59]
buprenorphine . A retrospective study evaluated the presence of the DRD2 TaqI A1 allele in treatment
[60]
response with methadone (n = 46, 57% males) and buprenorphine (n = 25, 68% females) . The patient
population was mostly composed of Australians with European ancestry (88%). No significant associations
were found related to buprenorphine dose or response, although methadone patients who were DRD2 TaqI
A1 carriers experienced less withdrawal symptoms than non-carriers (P = 0.04).

[55]
The previously mentioned study by Gerra et al. also evaluated the presence of different alleles at the
dopamine transporter gene (SLC6A3/DAT1) on buprenorphine response. As mentioned, participants (n
= 107, 81% males) were classified as responders or non-responders. Non-responders showed continuous
use of heroin, severe psychiatric distress, medication diversion and/or dropout of treatment. A significant
difference was observed between groups, as all carriers of the 11-repeat allele were able to complete
treatment for the duration of the study, without significant disturbances (P = 0.001). In addition, the
frequency of the 10-repeat allele was higher in non-responders (65% vs. 56%), but statistical significance
was not established.

Discussion
The research that exists to date, regarding the role of dopaminergic pharmacogenes on buprenorphine
[60]
therapeutics is still limited. The study of the DRD2 TaqI A1 allele by Barratt et al. was likely underpowered
to identify meaningful associations, particularly in the buprenorphine arm. However, their preliminary
[55]
findings in the methadone group suggest further research is justified. The results from Gerra et al.
suggest a potential clinical utility in SLC6A3/DAT1 variants that also warrants further study.

PHARMACOGENES: METABOLISM
The metabolic rate of drugs can vary between individuals, making dosing adjustments necessary to achieve
the desired effects. Buprenorphine is extensively metabolized in the liver via N-dealkylation by cytochrome
P450 (CYP450) enzymes, producing nor-buprenorphine, the major active metabolite [61,62] . To a lesser
extent, both buprenorphine and nor-buprenorphine undergo glucuronidation by UGT [Figure 1]. CYP3A4
may be considered the primary CYP450 enzyme in the metabolism of buprenorphine, but other enzymes
involved have been identified. Using human liver microsomes, a study found that CYP3A4 and CYP2C8
[61]
were able to produce the active metabolite in considerable concentrations . CYP3A5 and CYP3A7 were
also identified as contributors in the metabolic pathway. Approximately 90% of buprenorphine was shown
to be metabolized by CYP3A enzymes, and thus, genetic variations due to ancestry and/or sex differences
in these enzymes may impact buprenorphine exposure . In addition to the CYP450 system, the UGT2B7
[63]