Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

Pregnancy Related Clinical Trial

— CAMCAP  

Official title:

Cholesterol and CYP3A4/5 Metabolism Across Pregnancy and Postpartum

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05504889
• Other study ID #: STU00217170
• Status: Completed
• Start date: June 17, 2022
• Est. completion date: June 30, 2023

Study information

• Verified date: April 2024
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: June 30, 2023
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Pregnancy Related

Locations

Country	Name	City	State
United States	Northwestern University Asher Center for the Study and Treatment of Depressive Disorders	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Northwestern University	Purdue University

Country where clinical trial is conducted

United States, 

References & Publications (7)

Bergstrom H, Helde Frankling M, Klasson C, Lovgren Sandblom A, Diczfalusy U, Bjorkhem-Bergman L. CYP3A Activity in End-of-Life Cancer Patients Measured by 4beta-Hydroxycholesterol/cholesterol Ratio, in Men and Women. Cancers (Basel). 2021 Sep 18;13(18):4689. doi: 10.3390/cancers13184689. — View Citation

Bjorkhem-Bergman L, Backstrom T, Nylen H, Ronquist-Nii Y, Bredberg E, Andersson TB, Bertilsson L, Diczfalusy U. Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. Drug Metab Dispos. 2013 Aug;41(8):1488-93. doi: 10.1124/dmd.113.052316. Epub 2013 May 14. — View Citation

Kim AH, Kim B, Rhee SJ, Lee Y, Park JS, Lee SM, Kim SM, Lee S, Yu KS, Jang IJ, Cho JY. Assessment of induced CYP3A activity in pregnant women using 4beta-hydroxycholesterol: Cholesterol ratio as an appropriate metabolic marker. Drug Metab Pharmacokinet. 2018 Jun;33(3):173-178. doi: 10.1016/j.dmpk.2018.04.004. Epub 2018 Apr 25. — View Citation

Naito T, Kubono N, Ishida T, Deguchi S, Sugihara M, Itoh H, Kanayama N, Kawakami J. CYP3A activity based on plasma 4beta-hydroxycholesterol during the early postpartum period has an effect on the plasma disposition of amlodipine. Drug Metab Pharmacokinet. 2015 Dec;30(6):419-24. doi: 10.1016/j.dmpk.2015.08.008. Epub 2015 Sep 3. — View Citation

Nylen H, Sergel S, Forsberg L, Lindemalm S, Bertilsson L, Wide K, Diczfalusy U. Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4beta-hydroxycholesterol. Eur J Clin Pharmacol. 2011 Jul;67(7):715-22. doi: 10.1007/s00228-010-0984-1. Epub 2011 Jan 19. — View Citation

Penzak SR, Rojas-Fernandez C. 4beta-Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation. J Clin Pharmacol. 2019 May;59(5):611-624. doi: 10.1002/jcph.1391. Epub 2019 Feb 12. — View Citation

Tomalik-Scharte D, Lutjohann D, Doroshyenko O, Frank D, Jetter A, Fuhr U. Plasma 4beta-hydroxycholesterol: an endogenous CYP3A metric? Clin Pharmacol Ther. 2009 Aug;86(2):147-53. doi: 10.1038/clpt.2009.72. Epub 2009 May 20. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the endogenous metabolic ratio of 4ß-hydroxycholesterol to cholesterol (4ß-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	Impact of active CYP3A5 phenotype on the 4ß-hydroxycholesterol to cholesterol metabolic ratio	plasma concentrations	Between 4-13 weeks of pregnancy, and 1-18 weeks postpartum
Secondary	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