Pregnancy Related
Conditions
Keywords
pregnancy, CYP3A, postpartum, hydroxycholesterol ratio
Brief summary
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
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.
Interventions
None listed
Sponsors
Purdue University
Northwestern University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | plasma concentrations |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Impact of active CYP3A5 phenotype on the 4β-hydroxycholesterol to cholesterol metabolic ratio | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | plasma concentrations |
| Impact of estradiol concentrations on ratio in the early first trimester of pregnancy | Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum | plasma concentrations |
Countries
United States
Outcome results
None listed