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.
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