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    Research Grants Awarded

    Clinical Assessment of Cytochrome P450 (CYP)3A4 Induction by Tamoxifen: Potential Impact of Hormonal and Genetic Factors

    Study Section:

    Scientific Abstract:
    Background: Tamoxifen (TAM) is an effective endocrine agent for adjuvant therapy and chemoprevention of breast cancer. However, there is marked inter-subject variability in its pharmacokinetics (PK) and in its safety and efficacy profiles. Other unresolved issues include drug-drug interactions (DDIs), development of resistance and elevated risk for endometrial carcinogenesis. TAM undergoes extensive metabolism by cytochrome P450 (CYP) enzymes. Most prominent contribution is made by CYP3A4, which catalyzes the formation of N-desmethylTAM (N-DMT), an inactive metabolite, and á-hydroxyTAM (á-OHT), which is implicated in the TAM-mediated endometrial carcinogenesis. In a recent study employing primary human hepatocytes we observed that TAM markedly induced CYP3A4 activity. Furthermore, transfection of human hepatocytes with siRNA against the human pregnane X receptor (hPXR), which regulates CYP3A4 transcription, abrogated the inductive effects indicating that hPXR is a key mediator of CYP3A4 induction by TAM. Also, presence of activated estrogen receptor suppressed the hPXR activity. Most importantly, in a pilot study we noted an increase in CYP3A4 activity in 3 out of 4 patients on TAM therapy. Objectives/hypothesis: Based on our above-indicated findings, we propose to test the hypothesis that TAM therapy leads to induction of CYP3A4 in women and that genetic variability and hormonal levels influence the extent of induction. Specific Aims: 1) To evaluate the extent to which tamoxifen induces CYP3A4 in women initiating TAM therapy and alters its own metabolism and that of co-administered CYP3A4 substrates. 2) To conduct preliminary assessment of the impact of genetic variability and hormonal levels on CYP3A4 induction by TAM. Study Design: Women initiating TAM as primary or post surgery adjuvant therapy or for chemoprevention will be enrolled in this trial (n = 32; 28 in addition to 4 who have already participated). Midazolam (MDZ), a drug exclusively metabolized by CYP3A4, will be used as a probe for enzyme function. Changes in PK of MDZ and TAM and its metabolites will be determined at different stages during the therapy. Blood samples will be obtained for genetic and hormonal analysis. Potential Outcome and Benefits of the Research: This study will elucidate the risk for DDIs and increased TAM metabolism resulting from CYP3A4 induction in women on TAM therapy. Differences in the extent of induction and the production of N-DMT and á-OHT will be underscored. This study also represents a first step to assess the impact of genetic variability and hormonal levels on CYP3A4 induction by TAM, which will form the basis for a larger, prospectively designed trial. Overall, these studies will aid in optimizing TAM use with drugs that are CYP3A4 substrates such as aromatase inhibitor. Our findings will also aid in screening subjects based on genotyping and hormonal status who are likely to have higher levels of N-DMT or á-

    Lay Abstract:
    Background: Tamoxifen (TAM) is a widely used anti-estrogen in the treatment and prevention of breast cancer. It has been credited with saving lives of numerous breast cancer patients. However, its use is associated with several problems including: a) large variability in TAM levels among patients, which contributes to differences in the therapeutic benefits and adverse effects and b) drug-drug interactions. An enzyme known as CYP3A4 plays a central role in the metabolism (conversion) of TAM leading to the formation of an inactive compound, N-DMT, and a toxic compound, á-OHT, which is linked to endometrial cancer in women. Individuals with higher amounts of N-DMT may have diminished TAM efficacy and those with higher á-OHT levels may be at higher risk for endometrial cancer. Several drugs are known to induce (increase the quantity and activity) CYP3A4 thereby enhancing the metabolism of co-medications and leading to drug interactions. They may also enhance their own metabolism and since individuals differ in their capacity to induce CYP3A4, induction contributes significantly to the above-indicated variability. Objectives/Hypothesis: The hypothesis of our study is that TAM induces CYP3A4 in humans and that genetic and hormonal background of an individual impact this inductive effect. This is based on extensive work done using human liver cells and a small clinical study, where we observed that TAM increased the CYP3A4 activity in 3 out of 4 breast cancer patients. We now propose to extend these novel findings to include a larger number of women to obtain a clear assessment of the effects of TAM on CYP3A4 activity. Specific Aims: We will assess CYP3A4 function and measure the levels of TAM metabolites before and during TAM therapy. We will also conduct preliminary analyses to explore if difference in the observed extent of CYP3A4 induction can be explained on the basis of genetic or hormonal variations. Study Design: We will enroll 32 subjects. The CYP3A4 activity will be measured before starting, and after short term and long term TAM therapy. Blood samples will also be collected to measure TAM and its metabolites, estradiol levels and for genetic analysis. Potential Outcomes and Benefits of the Research: Firstly, our study will aid in selecting drugs that are least likely to interact with TAM. Secondly, it will indicate whether the levels of N-DMT and á-OHT increase during the course of TAM therapy. Thirdly, it will help in understanding why women differ in the extent of CYP3A4 induction. A detailed analysis of the reasons for the variability will require a much larger clinical trial, which will be undertaken based on results from this study. Ultimately, these attempts will aid in ?personalizing? the use of TAM and seeking alternative therapies for subjects likely to be at risk for drug interactions and adverse effects of TAM