Two examples described here underscore the importance of understanding the cytochrome P450 (CYP) system
MENTAL HEALTH MINUTE
What happens at the molecular level in patients after they ingest a medication? Over the past 30 years, psychiatry has come a long way, especially in better understanding the importance of considering the cytochrome P450 (CYP) system when prescribing medications.
To best understand these issues, it is helpful to look at clinical examples. Consider a patient who has been diagnosed with breast cancer and is being treated with tamoxifen. Tamoxifen, a prodrug, binds poorly to the estrogen receptor, which is the treatment target. The drug has to undergo metabolism through the cytochrome P450 2D6 (CYP2D6) pathway to be transformed into its 2 active metabolites: 4-hydroxytamoxifen and endoxifen. Both metabolites have approximately 100 times more potency at the estrogen receptor than tamoxifen and are considered the active treatment molecules.
In psychiatry, we have 3 commonly prescribed antidepressants—fluoxetine, paroxetine, and bupropion—that very potently inhibit CYP2D6. If a patient is on 1 of these 3 antidepressants as well as tamoxifen, the drug-drug interaction prevents the conversion of the tamoxifen to its active metabolites. In other words, the patient will not receive the benefits of that treatment. If the patient also is genotypically an extensive, intermediate, or a poor metabolizer at the CYP2D6 pathway and 1 of these 3 antidepressants have been prescribed, the CYP2D6 pathway is completely knocked out. The end result is no clinical activity from the tamoxifen, and any benefits of the treatment is negated. This is one dramatic example of how understanding drug-drug interactions at the CYP system can be clinically relevant.
Another example can be found in the underappreciated opioid medication arena. We know that codeine has very little activity at the mu opioid receptor. When codeine goes through the cytochrome P450 2D6 metabolic pathway, it gets metabolized to morphine, which is roughly 20 times more potent than codeine. The FDA product insert for codeine has a black box warning stating that if a patient is an ultra-rapid metabolizer (approximately 1% of the population) at CYP2D6, the patient is then at risk of respiratory depression and death due to the rapid metabolism of codeine to the much more potent morphine. If a patient is prescribed codeine and they are a poor metabolizer at CYP2D6, or if they are simultaneously taking 1 of those 3 antidepressants that inhibit CYP2D6, most of the codeine will not be metabolized to morphine and the patient may report no analgesic effect. This is important considering some patients engage in malingering and drug-seeking behaviors; the decreasedanalgesia described by the patient may simply be the consequence of not receiving adequate blood levels of morphine.
This pharmacology extends to 2 other commonly prescribed analgesics: hydrocodone and oxycodone. Both are prodrugs with some analgesic properties, but they are both metabolized by the CYP2D6 enzyme system to their more potent active metabolites hydromorphone and oxymorphone, respectively. As with codeine and morphine, the patient’s CYP2D6 phenotype as well as the presence or absence of any fluoxetine, paroxetine, or bupropion can create a wide range of analgesia that can differ dramatically from patient to patient.
Thus, it is always important to consider the cytochrome P450 pathways when prescribing medications, as the results can be widely different than what you expect.
Dr Miller is Medical Director, Brain Health, Exeter, NH; Editor in Chief, Psychiatric TimesTM; Staff Psychiatrist, Seacoast Mental Health Center, Exeter, NH; Consulting Psychiatrist, Exeter Hospital, Exeter, NH; Consulting Psychiatrist, Insight Meditation Society, Barre, MA.
This article was originally posted on June 26, 2020, and has since been updated. -Ed
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