There are a number of physiologic changes that can impact the efficacy and safety of medication use in pregnancy. One such change involves alterations in the activities of some drug-metabolizing enzymes. These changes compound the impact that existing genetic polymorphisms can have on enzyme activity. These two important variables impact the pharmacokinetics and pharmacodynamics of certain medications.
A majority of drug-metabolizing enzymes, including CYP2D6, CYP2B6, CYP2C9, and CYP3A5, show an increase in activity during pregnancy. While this is the trend for many of the CYP enzymes, there are enzymes that have a contrary effect. CYP1A2 and CYP2C19 both show decreased activity during pregnancy. Depending on the effect of pregnancy on an enzyme’s activity, the risk of inefficacy or development of adverse drug reactions may be of concern.
Looking specifically at CYP2D6, this drug-metabolizing enzyme is highly polymorphic, and it influences approximately 25% of medication’s metabolic pathways. During the second trimester of pregnancy, the activity of CYP2D6 in normal and ultrarapid metabolizers begins to rise. This rise continues into the third trimester. While ultrarapid metabolizers already have increased enzyme activity, this effect can be further compounded. Ondansetron, which is sometimes used during pregnancy to treat severe or refractory nausea and vomiting, is metabolized by CYP2D6 to its less active form. Pregnant individuals who are ultrarapid metabolizers can experience treatment failure due to decreased exposure of ondansetron. As a result, an alternative medication may be required. Codeine is another drug that is metabolized by CYP2D6. As a prodrug, codeine is converted to its active form of morphine. Increased activity in normal and ultrarapid metabolizers during pregnancy can cause increased exposure to morphine. Consequently, the use of codeine during pregnancy should be limited. This can also be of concern after pregnancy in breastfeeding women who are ultrarapid metabolizers. Deaths have occurred in breastfeeding infants due to high morphine exposure.
CYP2C19 is another major metabolizing enzyme that is highly polymorphic. As opposed to most CYP enzymes, CYP2C19 has shown decreased activity during pregnancy. This enzyme is involved in the metabolism of proton pump inhibitors, such as omeprazole, which are commonly taken during pregnancy. While the efficacy of these drugs may improve with decreased CYP2C19 activity, there is an increased risk in adverse drug reactions such as hepatotoxicity.
While pharmacogenomic data including pregnant women is not robust, current studies help provide a framework for possible pharmacogenomic interventions that may improve efficacy and prevent adverse events in commonly prescribed medications used during pregnancy.
Sources:
1. Betcher HK, George AL Jr. Pharmacogenomics in pregnancy. Semin Perinatol. 2020;44(3):151222.
2. Eke AC. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics. J Basic Clin Physiol Pharmacol. 2021;33(5):581-598.
3. Obeng AO, Rouby N, Liu M, Wallsten R. Important preparatory steps and clinical considerations for pharmacogenetics adoption into practice. J Transl Genet Genom. 2021;5:64-79.
Nicholas Klouvas is a PharmD/MS in Pharmacogenomics Candidate on rotation, and Cathryn Jennissen, PharmD, BCOP is currently the Senior Clinical Pharmacist at OneOme LLC, a med tech company in Minneapolis, MN. OneOme offers additional information and PGx education which can be found at OneOme.com/education or you may reach out to support@oneome.com
