Hepatic drug metabolism enzymes that are catalyzed by cytochrome P- 4503A4 (CYP3A4 enzymes) are responsible for metabolizing a large number of therapeutic agents, including estradiol.
The specific aims of the project are (1) to examine the ethnic differences in drug metabolism mediated by CYP3A4 enzyme in pre-menopausal healthy women; (2) to examine the ethnic differences in drug metabolism mediated by CYP3A4 enzyme in post-menopausal healthy women; and (3) to examine the age- related metabolic differences of CYP3A4 enzyme in healthy women. CYP3A4 activity will be assessed using dapsone as the probe drug. Thirty-six women, divided equally into three groups, will be enrolled in one of two studies based on age, ethnicity and menopausal status. The study will comprise pre-menopausal African-American (A-A) and Caucasian (CA) women (20-39 years) who are not taking oral contraceptives (n=12); and the second study will comprise postmenopausal A-A and CA women who are 45-54 years old (N=12), and post-menopausal A-A and CA women who are 55-65 years old (n=12). All ethnic groups will be matched for age and weight. Subjects' vital signals will be measured and recorded. Dapsone and metabolite concentrations in urine and plasma, following drug administration, will be determined by a validated HPLC method. Estradiol concentrations also will be determined. Pharmacokinetic parameters will be determined and statistically compared. It is postulated that if ethnic differences in the metabolic activity of CYP3A4 exists, then future studies of other drugs including agents to treat HIV such as the protease inhibitors which are metabolized by CYP3A4, will be warranted.
|Shimada, Tsutomu; Takenaka, Shigeo; Kakimoto, Kensaku et al. (2016) Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. Chem Res Toxicol 29:1029-40|
|Shimada, Tsutomu; Takenaka, Shigeo; Murayama, Norie et al. (2016) Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13. Xenobiotica 46:211-24|
|Liu, Jiawang; Pham, Peter T; Skripnikova, Elena V et al. (2015) A Ligand-Based Drug Design. Discovery of 4-Trifluoromethyl-7,8-pyranocoumarin as a Selective Inhibitor of Human Cytochrome P450 1A2. J Med Chem 58:6481-93|
|Goyal, Navneet; Liu, Jiawang; Lovings, La'Nese et al. (2014) Ethynylflavones, highly potent, and selective inhibitors of cytochrome P450 1A1. Chem Res Toxicol 27:1431-9|
|Liu, Jiawang; Taylor, Shannon F; Dupart, Patrick S et al. (2013) Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1. J Med Chem 56:4082-92|
|Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF CARBAZOLE ANALOGS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:92-95|
|Foroozesh, Maryam; Jiang, Quan; Sridhar, Jayalakshmi et al. (2013) DESIGN, SYNTHESIS, AND EVALUATION OF A FAMILY OF PROPARGYL PYRIDINYL ETHERS AS POTENTIAL CYTOCHROME P450 INHIBITORS. J Undergrad Chem Res 12:91-94|
|Shimada, Tsutomu; Kim, Donghak; Murayama, Norie et al. (2013) Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition. Chem Res Toxicol 26:517-28|
|Liu, Jiawang; Sridhar, Jayalakshmi; Foroozesh, Maryam (2013) Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules 18:14470-95|
|Liu, Jiawang; Nguyen, Thong T; Dupart, Patrick S et al. (2012) 7-Ethynylcoumarins: selective inhibitors of human cytochrome P450s 1A1 and 1A2. Chem Res Toxicol 25:1047-57|
Showing the most recent 10 out of 34 publications