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Arroyo Seguí et al. J Transl Genet Genom 2020;4:263-77 I http://dx.doi.org/10.20517/jtgg.2020.35 Page 269

Figure 1. The metabolic pathways of buprenorphine. *Variants of this gene have been found to be clinically relevant

[64]
gene has been identified as playing a minor role in buprenorphine metabolism . In a study with
human liver microsomes, the presence of the UGT2B7 promoter (G-842A) mutation resulted in higher
buprenorphine glucuronidation V (80% on average) and a higher glucuronidation rate in non-carriers (but
max
not in carriers) of the UGT1A1*28 allele (P = 0.0352).

Phenotypic classifications have been developed to categorize functional variants of CYP3A4, as poor (PM),
[65]
intermediate (IM), extensive (EM), or ultrarapid (UM) metabolizers . Without dose adjustments, poor
metabolizers may have higher than normal plasma levels of buprenorphine, potentially increasing the risk
for adverse events. Similarly, ultrarapid metabolizers may have lower plasma levels, which may induce
opioid cravings and/or withdrawal symptoms. This particular scenario was observed in a case report
[65]
involving an African American male undergoing OUD management with buprenorphine/naloxone .
During every medical appointment, a urine screening was performed to assess adherence and detect
the use of unauthorized or illicit substances. This patient had no significant socioeconomic barriers (i.e.,
married, stable home and employed) and was being treated with a buprenorphine daily dose of 28 mg. For
a few years the patient was adherent with no use of other opioids, although occasionally used synthetic
cannabinoids. However, following a dosage decrease to 24 mg due to a change in insurance coverage,
the patient reported withdrawal symptoms and had multiple recurrences with morphine, methadone,
benzodiazepines and synthetic cannabinoids. Pharmacogenomic testing found the patient to have a
CYP3A4*1/*1B diplotype, which has been associated with an increased metabolic rate [66,67] . Less than a year
later, the third-party payer dose-limiting policy was cancelled and the patient went back to 28 mg for one
month, and then increased to 32 mg. During the next 4 months with 32 mg, the patient did not use any
unauthorized substances. As a CYP3A4*1B carrier, the patient was classified as an ultrarapid metabolizer,
consistent with a higher dose requirement.

The same research group then conducted a retrospective cohort study to evaluate CYP3A4 and CYP3A5
polymorphisms on buprenorphine response (i.e., dosing, withdrawal and relapse) . The patient population
[67]
was mostly composed of African Americans (n = 111/113, 76% males). Participants were classified
by their CYP3A4 phenotype, and the majority of the patient population were ultrarapid metabolizers
(82%), carrying at least one *1B allele. Clinical outcomes assessed included withdrawal instances, use of