Greater than 50% of pregnant women take at least one prescription drug. Drug selection, dosing, and monitoring are important for all patients. However, the intricacies of physiological changes during pregnancy and the implications of drug therapy on the health and well-being of pregnant mothers and the developing fetus complicate treatments during gestation. Clinical evidence informs us that pregnancy alters hepatic drug metabolism, but the causative factors responsible for this phenomenon remain to be identified. Pregnancy increases elimination of cytochrome P450 (CYP)2A6, -2C9, -2D6, or -3A4 substrate drugs, while decreasing elimination of CYP1A2 or -2C19 substrates. Of the physiological changes associated with pregnancy, most pronounced is a dramatic increase in the production of female hormones, i.e., estrogens and progesterone (PRG). Preliminary results from our laboratory indicate that estradiol (E2) modulates expression of CYP1A2 and -2A6 whereas PRG upregulates CYP2A6 and -3A4 in human hepatocytes. For these CYP enzymes, the directional changes in their expression are similar to the clinically reported pharmacokinetic changes, suggesting that female hormones may be in part responsible for the changes in drug metabolism during pregnancy. Of note, E2 and PRG do not recapitulate all the changes in drug metabolism during pregnancy, such as induction of CYP2D6 activity. This indicates that as yet unknown factors regulate CYP expression during pregnancy. Preliminary data from our laboratory indicate presence of such factors in pregnant women's plasma. The central hypothesis of this project is that physiological changes accompanying pregnancy modulate CYP expression, leading to altered drug metabolism. The following specific aims are proposed: (1) Characterize combined effects of female hormones on CYP expression and drug metabolism. (2) Elucidate regulatory mechanisms for CYP3A4 induction by PRG. (3) Identify regulatory mechanisms for CYP2D6 induction during pregnancy. (4) Establish a model system to study altered drug metabolism during pregnancy, using human hepatocytes incubated in pregnant women's plasma. The proposed studies will enable us to identify and characterize pregnancy-relevant factors that are responsible for altered drug metabolism during pregnancy, establish their effects on CYP expression, and determine the underlying regulatory mechanisms for two clinically most important CYP enzymes, CYP2D6 and CYP3A4. The complex physiological changes during pregnancy and the consequences of drug exposure to mothers and their developing fetuses underscore the importance of elucidating potential mechanisms for the regulation of drug metabolism during pregnancy. Our preliminary work in this area and the studies proposed herein will ultimately help us accurately predict pharmacokinetic changes of drugs in pregnant women. This information will have a valuable impact on drug selection and dosing during pregnancy.

Public Health Relevance

Medication use by pregnant women is common, and drug behaviors in this population are generally different from those in non-pregnant women or men. Understanding of these changes is important in determining optimal dosing regimen. We propose to investigate what causes the changes in drug behaviors and study the underlying mechanisms. The knowledge obtained from this study can be expanded to optimize drug therapy in other groups of women, such as oral contraceptive users, thus benefiting women in general.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD065532-02
Application #
8239928
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (50))
Program Officer
Ren, Zhaoxia
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$337,962
Indirect Cost
$108,239
Name
University of Illinois at Chicago
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Cho, Sung-Joon; Ning, Miaoran; Zhang, Yanyan et al. (2016) 17β-Estradiol up-regulates UDP-glucuronosyltransferase 1A9 expression via estrogen receptor α. Acta Pharm Sin B 6:504-509
Ning, Miaoran; Koh, Kwi Hye; Pan, Xian et al. (2015) Hepatocyte nuclear factor (HNF) 4α transactivation of cytochrome P450 (Cyp) 2d40 promoter is enhanced during pregnancy in mice. Biochem Pharmacol 94:46-52
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Zhang, Shu; Pan, Xian; Jeong, Hyunyoung (2015) GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression. Drug Metab Dispos 43:743-8
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Pan, Xian; Jeong, Hyunyoung (2015) Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice. Mol Pharmacol 88:106-12
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Koh, Kwi Hye; Pan, Xian; Zhang, Wei et al. (2014) Krüppel-like factor 9 promotes hepatic cytochrome P450 2D6 expression during pregnancy in CYP2D6-humanized mice. Mol Pharmacol 86:727-35

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