Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

Study Overview
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Brief Summary
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This study addresses the second aim of the grant (R01 HD0899455), which is to determine temporal changes in CYP3A4-mediated drug metabolism sequentially across pregnancy and after birth.

Detailed Description
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This study addresses the second aim of the grant (R01 HD0899455), which is to determine temporal changes in CYP3A4-mediated drug metabolism sequentially across pregnancy and after birth. In studies with human hepatocytes, we found that serum from women in the first trimester led to the highest CYP3A4 expression compared to those from the second or third trimester or after birth. Among the hormones with elevated plasma concentrations in early pregnancy, our studies revealed that thyroid hormone enhances CYP3A4 expression in human hepatocytes. Based on the results, we hypothesized that CYP3A4-mediated drug metabolism is highest during early pregnancy (compared to the later time points of pregnancy or postpartum period) in part due to changes in thyroid hormone concentration. To test this hypothesis, we will evaluate the conversion of endogenous cholesterol to its 4β-hydroxycholesterol metabolite, which is facilitated by CYP3A4. To assess additional factors that affect CYP3A activity, we will obtain DNA. About 75% of African Americans, but only 10-20% of people of European descent, carry the active allele CYP3A5*1, which significantly increases the clearance of many CYP3A4/5 substrates, including the conversion of cholesterol to 4β-hydroxycholesterol.

Official Title
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Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

Conditions
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Pregnancy Related

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: English speaking Pregnant before 14w0d OR postpartum between before 18w0d Singleton gestation (as this will result in more consistent inter-individual measures) Exclusion Criteria: Chronic use of compounds that are substrates or inhibitors of CYP3A4 inhibitors, which will interfere with the concentrations and ratio. Potent inhibitors include clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit. Inducers of CYP3A4 include phenobarbital, phenytoin, rifampicin, St. John's Wort and glucocorticoids. Diagnosis of alcoholism or substance use. Covid infection or within 4 weeks of positive test due to possible effect on hepatic function

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| OPTIMOM residual samples<br>Residual plasma samples collected in one of our prior studies monthly across pregnancy (OPTIMOM, NICHD 1U54HD085601-01, Clinical Trials.gov ID NCT02519790; K. Wisner, PI) will be evaluated for cholesterol and 4β-hydroxycholesterol. These samples were obtained from women who gave their consent for use of their blood samples for future studies. All OPTI-MOM participants have been genotyped for variants in CYP3A5 using commercial allelic discrimination assays (ThermoFisher Scientific, Waltham, MA, with Taqman probes.) | |
| Newly recruited subjects<br>Plasma samples will be collected from newly recruited subjects. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the endogenous metabolic ratio of 4β-hydroxycholesterol to cholesterol (4β-OHC/C, a marker of CYP3A activity) from early pregnancy through 17 weeks 6 days after delivery | plasma concentrations | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of active CYP3A5 phenotype on the 4β-hydroxycholesterol to cholesterol metabolic ratio | plasma concentrations | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | 
| Impact of estradiol concentrations on ratio in the early first trimester of pregnancy | plasma concentrations | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pregnancy, CYP3A, postpartum, hydroxycholesterol ratio