AOR guarantees that no ingredients not listed on the label have been added to the product. Contains no wheat, gluten, corn, nuts, dairy, soy, eggs, fish or shellfish.

Suggested Use
Take one capsule twice a day. Do not take I•3•C 200 at the same time as antacids, H2-receptor blockers (eg. Zantac®), or proton-pump inhibitors (eg. Nexium®), as these drugs may impede the conversion of I3C to some active metabolites. Or as directed by a qualified health consultant.

Main Applications
As reported by literature:
• Safer estrogen metabolism.
• Risk reduction for women's cancers.
• Respiratory Papillomatosis (RP)

Source
Synthesis from indole.

Pregnancy / Nursing
No studies have been conducted. Best to avoid.

Cautions
Do not take I•3•C 200^TM at the same time as antacids, H2-receptor blockers (eg. Zantac®), or proton-pump inhibitors (eg. Nexium®). I3C may change the bioavailability of many drugs, including methadone, cyclosporine, codeine, statin drugs, and most of the protease inhibitors used to treat HIV. Consult with a qualified health care practitioner if you are taking any medications before taking I3C. do not use if you are pregnant or nursing. Always have regular mammograms and Pap smears and do not attempt to self-diagnose or self-medicate reproductive cancers.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Copyright © 2005, Advanced Orthomolecular Research

Suppression of mammary gland carcinogenesis by post-initiation treatment of rats with tamoxifen or indole-3-carbinol or their combination.
Eur J Cancer Prev. 2007 Apr;16(2):130-41.
Malejka-Giganti D, Parkin DR, Bennett KK, Lu Y, Decker RW, Niehans GA, Bliss RL.

This study examined whether suppression of mammary gland carcinogenesis elicited by low doses of tamoxifen (TAM) can be enhanced by concomitant treatment of rats with indole-3-carbinol (I3C), a component of cruciferous vegetables and a dietary supplement used for its putative antiestrogenicity. Two weeks after one oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) at 65 mg/kg body weight, female Sprague-Dawley rats started treatment with TAM (10 microg/rat) by subcutaneous injection, I3C (250 mg/kg body weight) by oral gavage, TAM+I3C or their respective vehicles three times per week, for up to 20 weeks. Significant increases in the median latency of malignant mammary tumors and decreases in the mean tumor mass per rat were due to TAM. Significant decreases in the mean tumor number per rat in TAM, I3C and TAM+I3C-treated rats indicated a cooperative effect of the two compounds. In both DMBA-initiated and uninitiated rats, significant increases in the ratios of liver to body weight in I3C and TAM+I3C-treated groups coincided with I3C-dependent increases of hepatic cytochrome P450 levels and activities (1A1, 1A2 and 2B1/2). The ratios of uterus to body weight decreased with the number of treatments and the decreases effected by TAM were greater than those by I3C. The levels of circulating estrone were increased in response to I3C treatment and were greater in DMBA-initiated rats than in uninitiated rats, which may contribute to the preventive effect of I3C. Chemoprevention may be accomplished through up-regulation of apoptotic enzyme (caspase) activities in the mammary gland or mammary tumors. Treatment with TAM, I3C or TAM+I3C had no effect on caspase-3&7, caspase-6, caspase-8 and caspase-9 activities in the mammary tumors or mammary gland of tumor-bearing rats or that of uninitiated rats. In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities, suggesting an I3C-mediated protective effect. Even though I3C alone is a much less effective suppressing agent of mammary carcinogenesis than TAM, I3C in combination with TAM does not weaken but may foster the benefits of chemoprevention with TAM.

EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells.
Carcinogenesis. 2007 Feb;28(2):435-45. Epub 2006 Sep 6.
Moiseeva EP, Heukers R, Manson MM.

Indole-3-carbinol (I3C), a dietary chemopreventive compound, induced marked reduction in epidermal growth factor receptor (EGFR) prior to cell death in cells representing three breast cancer subtypes. Signalling pathways, linking these events were investigated in detail. I3C modulated tyrosine phosphorylation from 30 min in four cell lines. In MDA-MB-468 and HBL100 cells, it induced Src activation after 5 h. In MDA-MB-468 cells, I3C induced signalling between 4.5 and 7 h, which involved sequential activation of Src, EGFR, STAT-1 and STAT-3, followed by EGFR degradation. It also induced physical association between activated Src and EGFR. In MCF7 and MDA-MB-231 cells, I3C modulated expression of cell cycle-related proteins, p21Cip1, p27Kip1, cyclin E, cyclin D1 and CDK6, with upregulation of p21Cip1 and cyclin E being dependent on Src. Inhibition of EGFR by specific inhibitors PD153035 or ZD1839 increased susceptibility to I3C-induced apoptosis of MCF7, MDA-MB-468 and MDA-MB-231 cells. Inhibition of Src sensitized MDA-MB-468 and MDA-MB-231 cells to I3C, whereas overexpression of c-Src increased resistance to I3C in MDA-MB-468 and HBL100 cells. Modulation of Src in MDA-MB-468 cells influenced the basal level of EGFR expression and cell viability; the latter being positively correlated with EGFR activation levels. Therefore, EGFR and Src activities are essential for I3C-induced cell cycle arrest and death; however, I3C-induced pathways depend on specific features of breast cancer cells. The cancer types, which rely on 'EGFR addiction' or Src deregulation, are likely to be susceptible to I3C.

Placebo-controlled trial of indole-3-carbinol in the treatment of CIN.
Gynecol Oncol 2000 Aug; 78(2): 123-9.
Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrera EA, Mathis JM.

OBJECTIVE: Most precancerous lesions of the cervix are treated with surgery or ablative therapy. Chemoprevention, using natural and synthetic compounds, may intervene in the early precancerous stages of carcinogenesis and prevent the development of invasive disease. Our trial used indole-3-carbinol (I-3-C) administered orally to treat women with CIN as a therapeutic for cervical CIN [Cervical Intraepithelial Neoplasia: precancerous lesions of the cervix].
METHODS: Thirty patients with biopsy proven CIN II-III were randomized to receive placebo or 200, or 400 mg/day I-3-C administered orally for 12 weeks. If persistent CIN was diagnosed by cervical biopsy at the end of the trial, loop electrocautery excision procedure of the transformation zone was performed. HPV status was assessed in all patients.
RESULTS: None (0 of 10) of the patients in the placebo group had complete regression of CIN. In contrast 4 of 8 patients in the 200 mg/day arm and 4 of 9 patients in the 400 mg /day arm had complete regression based on their 12-week biopsy. This protective effect of I-3-C is shown by a relative risk (RR) of 0.50 ((95% CI, 0. 25 to 0.99) P = 0.023) for the 200 mg /day group and a RR of 0.55 ((95% CI, 0.31 to 0.99) P = 0.032) for the 400 mg/day group. HPV was detected in 7 of 10 placebo patients, in 7 of 8 in the 200 mg /day group, and in 8 of 9 in the 400 mg/day group.
CONCLUSIONS: There was a statistically significant regression of CIN in patients treated with I-3-C orally compared with placebo. The 2/16 alpha-hydroxyestrone ratio changed in a dose-dependent fashion. Copyright 2000 Academic Press.

Dose-ranging study of indole-3-carbinol for breast cancer prevention.
J Cell Biochem Suppl 1997; 28-29: 111-6.
Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne MP.

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.

Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.
J Natl Cancer Inst 1997 May 21; 89(10): 718-23.
Michnovicz JJ, Adlercreutz H, Bradlow HL.

BACKGROUND: The oxidative metabolism of estrogens in humans is mediated primarily by cytochrome P450, many isoenzymes of which are inducible by dietary and pharmacologic agents. One major pathway, 2-hydroxylation, is induced by dietary indole-3-carbinol (I3C), which is present in cruciferous vegetables (e.g., cabbage and broccoli).
PURPOSE: Because the pool of available estrogen substrates for all pathways is limited, we hypothesized that increased 2-hydroxylation of estrogens would lead to decreased activity in competing metabolic pathways.
METHODS: Urine samples were collected from subjects before and after oral ingestion of I3C (6-7 mg/kg per day). In the first study, seven men received I3C for 1 week; in the second study, 10 women received I3C for 2 months. A profile of 13 estrogens was measured in each sample by gaschromatography-mass spectrometry.
RESULTS: In both men and women, I3C significantly increased the urinary excretion of C-2 estrogens. The urinary concentrations of nearly all other estrogen metabolites, including levels of estradiol, estrone, estriol, and 16alpha-hydroxyestrone, were lower after I3C treatment.
CONCLUSIONS: These findings support the hypothesis that I3C-induced estrogen 2-hydroxylation results in decreased concentrations of several metabolites known to activate the estrogen receptor. This effect may lower estrogenic stimulation in women. IMPLICATIONS: I3C may have chemopreventive activity against breast cancer in humans, although the long-term effects of higher catechol estrogen levels in women require further investigation.

Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol.
Int J Obes Relat Metab Disord 1998 Mar;22(3):227-9
Michnovicz JJ.

OBJECTIVE: To investigate whether the dietary phytochemical, indole-3-carbinol (13C), influences the level of estradiol 2-hydroxylation in obese women.
DESIGN: A clinical intervention study involving the ingestion of purified 13C, 400 mg, for two months.
SUBJECTS: Five healthy, overweight, premenopausal women (age: 35-47 y, body mass index (BMI): 27-53 kg/m2).
MEASUREMENTS: Two estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3), were measured by radioimmunoassay in untimed overnight urine samples, before and after ingestion of 13C.
RESULTS: The ratio of urinary estrogens, 2OHE1/E3, was significantly increased in obese women following 13C, reflecting induction of 2-hydroxylation in these women.
CONCLUSIONS: Obese premenopausal women experience increased estrogen 2-hydroxylation in response to the dietary agent, 13C, similar to non-obese women. This response to 13C may result in a hormonal milieu that helps reduce estrogen-dependent cancer risk.

Long-term responses of women to indole-3-carbinol or a high fiber diet.
Cancer Epidemiol Biomarkers Prev 1994 Oct-Nov;3(7):591-5
Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP.

We test the hypothesis that the estrogen metabolite ratio 2-OH-estrone:estriol can be raised via dietary indole-3-carbinol (I3C) and that this higher ratio can be sustained over a 3-month test period. We also explore the possible role of pure fiber on estradiol metabolism. Using a randomized clinical trial with three arms, each containing 20 subjects, arm 1 received 400 mg/day of I3C daily for 3 months, arm 2 received 20 g of alpha-cellulose daily for the same time period as a source of added fiber, and arm 3 received a placebo dose. Blood levels of a variety of biochemical parameters were measured. The urinary 2-OH-estrone:estriol estrogen metabolite ratio was measured monthly at the same time of the menstrual cycle. While no changes were observed in the control and alpha-cellulose-treated arms, a substantial mean increase in the ratio was observed in the I3C-treated arm at month 1; that increase was maintained over the 3-month time period. Three of the 20 subjects in this I3C-treated group differed from the others in that no significant change in the metabolite ratio was observed at any time point. The results suggest that I3C can serve to increase the 2-OH-estrone:estriol metabolite ratio in a sustained manner without detectable side effects and that some individuals may be resistant to such change.

Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol.
Nutr Cancer 1991; 16(1): 59-66.
Michnovicz JJ, Bradlow HL.

Research studies have demonstrated a strong association between estrogen metabolism and the incidence of breast cancer, and we have therefore sought pharmacological means of favorably altering both metabolism and subsequent risk. Indole-3-carbinol (I3C), obtained from cruciferous vegetables (e.g., cabbage, broccoli, etc.), is a known inducer of oxidative P-450 metabolism in animals. We investigated the effects in humans of short-term oral exposure to this compound (6-7 mg/kg/day over 7 days). We used an in vivo radiometric test, which provided a highly specific and reproducible measure of estradiol 2-hydroxylation before and after exposure to I3C. In a group of 12 healthy volunteers, the average extent of reaction increased by approximately 50% during this short exposure (p less than 0.01), affecting men and women equally. We also measured the urinary excretion of two key estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3). We found that the excretion of 2OHE1 relative to that of E3 was significantly increased by I3C, further confirming the ongoing induction of 2-hydroxylation. These results indicate that I3C predictably alters endogenous estrogen metabolism toward increased catechol estrogen production and may thereby provide a novel "dietary" means for reducing cancer risk.

Ligand-independent activation of estrogen receptor function by 3, 3'-diindolylmethane in human breast cancer cells.
Biochem Pharmacol 2000 Jul 15; 60(2): 167-77.
Riby JE, Chang GH, Firestone GL, Bjeldanes LF.

3,3'-Diindolylmethane (DIM), a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C), is a promising anticancer agent present in vegetables of the Brassica genus. We investigated the effects of DIM on estrogen-regulated events in human breast cancer cells and found that DIM was a promoter-specific activator of estrogen receptor (ER) function in the absence of 17beta-estradiol (E(2)). DIM weakly inhibited the E(2)-induced proliferation of ER-containing MCF-7 cells and induced proliferation of these cells in the absence of steroid, by approximately 60% of the E(2) response. DIM had little effect on proliferation of ER-deficient MDA-MB-231 cells, suggesting that it is not generally toxic at these concentrations. Although DIM did not bind to the ER in this concentration range, as shown by a competitive ER binding assay, it activated the ER to a DNA-binding species. DIM increased the level of transcripts for the endogenous pS2 gene and activated the estrogen-responsive pERE-vit-CAT and pS2-tk-CAT reporter plasmids in transiently transfected MCF-7 cells. In contrast, DIM failed to activate transcription of the simple E(2)- and diethylstilbesterol-responsive reporter construct pATC2. The estrogen antagonist ICI 182780 (7alpha-[9-[(4,4,5,5, 5-pentafluoropentyl)sulfonyl]nonyl]-estra-1,3,5(10)-triene-3, 17beta-diol) was effective against DIM-induced transcriptional activity of the pERE-vit-CAT reporter, which further supports the hypothesis that DIM is acting through the ER. We demonstrated that ligand-independent activation of the ER in MCF-7 cells could be produced following treatment with the D1 dopamine receptor agonist SKF-82958 [(+/-)6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepinehydrobromide]. We also demonstrated that the agonist effects of SKF-82958 and DIM, but not of E(2), could be blocked by co-treatment with the protein kinase A (PKA) inhibitor H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide). These results have uncovered a promoter-specific, ligand-independent activation of ER signaling for DIM that may require activation by PKA, and suggest that this major I3C product may be a selective activator of ER function.

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells.
Cancer Res. 1999 Mar 15;59(6):1244-51.
Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF, Firestone GL.

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer.

Multiple molecular targets of indole-3-carbinol, a chemopreventive anti-estrogen in breast cancer.
Eur J Cancer Prev. 2002 Aug;11 Suppl 2:S86-93.
Ashok BT, Chen YG, Liu X, Garikapaty VP, Seplowitz R, Tschorn J, Roy K, Mittelman A, Tiwari RK.

The mechanism of action of the anti-estrogen indole-3-carbinol (I3C), present in cruciferous vegetables, is being examined in our laboratory with a view to promote the use of this naturally occurring chemopreventive as an alternative to synthetic anti-estrogens in human breast cancer. Our previous results clearly demonstrated that despite its low affinity for the estrogen receptor (ER), I3C abrogated estradiol-mediated cellular and biochemical effects in estradiol-responsive cells and tissues. In an earlier report, we identified ER phosphorylation as one of the targets of I3C, and in this communication we describe the consequence of inhibition of ER phosphorylation. Estradiol-induced DNA-binding proteins that bound to several DNA responsive elements were inhibited by I3C and this effect was not at the level of DNA-protein physical interaction as inclusion of I3C in vitro in the reaction mix did not affect the binding. We analyzed the spectrum of genes induced by estradiol and modulated and/or intercepted by I3C. Our results conclude that although estradiol-mediated functions are affected by I3C, its biochemical targets are multiple and some of these may be modulated by the oligomeric products of I3C.

Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3'-diindolylmethane in sprague-dawley rats.
Toxicol Sci. 2003 Jul;74(1):10-21. Epub 2003 May 02.
Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE.

Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are naturally occurring dietary components found in cruciferous vegetables. In the stomach, I3C forms condensation products including DIM. I3C and DIM are marketed as dietary supplements, but little is known about the safety of long-term exposure. Rats were fed either control diet, 1 or 10x the current human dose of absorption-enhanced DIM [BioResponse DIM® (Indolplex®)] or 5-7x the maximal recommended dose of I3C. Experimental diets were fed continuously for 3 or 12 months or 2 months followed by control diet for 1 month. Results at 3 or 12 months were similar in most respects. No significant differences between groups were found in blood chemistry. A general decrease in serum enzyme levels in male rats was observed, perhaps indicative of a protective effect. Males fed I3C exhibited higher serum levels of 25-hydroxy-vitamin D3 (25OH-D3). There were no observable differences grossly or histologically between groups, although a high number of hyaline casts were found throughout the kidneys of all animals. In both sexes total hepatic CYP levels were significantly induced by I3C, but not by either dose of DIM. Induction of CYP1A1 and CYP1A2 in liver and CYP1A1 in colon was detected for both sexes fed I3C and the high dose of DIM. CYP3A2 was induced in females fed I3C or the high dose of DIM; males were induced with I3C, but not DIM. No induction of CYP1B1 in the colon was observed in either sex. Long-term exposure to DIM produced no observable toxicity, and comparison to I3C indicates that DIM is a markedly less efficacious inducer of CYP in the rat at doses relevant to human supplementation.

Effects of treatment of rats with indole-3-carbinol or 3,3'-diindolylmethane on the hepatic P450-dependent metabolism of estrogen and tamoxifen.
Cancer Epidemiol Biomarkers Prev. 2003 Oct; 11 Suppl:1215(AbsD111).
Malejka-Giganti D, Parkin DR, Ritter CL, Bliss RL.

Indole-3-Carbinol (I3C), present in cruciferous vegetables, has been reported to suppress cancer at estrogen-responsive sites. This effect is presumably mediated through modification by I3C of cytochrome P450 (CYP) complement and activities leading to estrogen detoxification. In our previous study, treatment of female Sprague-Dawley rats by oral gavage with I3C at 5, 25 and 250 mg/kg body weight (bwt) in ethanol:olive oil (1:4) for 4 to 10 days yielded dose-dependent increases in the hepatic P450 level, CYP1A1, 1A2 and 2B1/2 probe activities, and in the rates of microsomal oxidations of 17 b-estradiol (E2) to 2-hydroxy (OH)- E2, 2-OH-estrone (E1), 6a-OH-E2, 6b-OH-E2, estriol and 15a-OH-E2, and of E1 to 2-OH-E1, 2-OH-E2, 6(a+b)-OH-E1 and 6a-OH-E2. The 4-day treatment with the highest dose of I3C produced the largest increases in the rates of E2 or E1 metabolism, whereas the lowest dose had no effect. Since the action if I3C is, in part, ascribed to its acid-condensation product 3,3'-diindolylmethane (DIM), we examined the effects of a 4-day oral treatment of rats with DIM at 8.4 and 42 mg/kg bwt (or at an assumed 2 and 10%, respectively, conversion of I3C at 250mg/kg bwt). DIM at 42 but not at 8.4 mg/kg bwt effected only small increases of the hepatic CYP1A1 and 2B1/2 activities. By contrast to I3C, DIM effected significant decreases in the rates of metabolism of E2 to 4-OH-E2, 4-OH-E1, 6a-OH-E2 and 6(a+b)-OH-E1 (by 34,36,70 and 60%, respectively), and E1 to 6(a+b)-OH-E1 (by 40%), indicating that it inhibits CYP(s) catalyzing the formation of the potentially adverse estrogen metabolites. The differences between I3C and DIM in eliciting CYP-mediated responses suggest that DIM alone is not a key player in the mechanism of action of I3C [emphasis added]. We also examined whether the I3C-or DIM-effected changes in CYP-catalyzed reactions affect hepatic metabolism of tamoxifen (TAM), an antiestrogen for breast cancer prevention. After treatment with I3C or DIM at the above dose levels, the rates of formation of the microsomal metabolites of TAM: a-OH-TAM, 4-OH-TAM and TAM-N-oxide remained unchanged, and that of N-desmethyl-TAM increased ~3-fold only after I3C at 250mg/kg bwt. The data suggest that oral intake of I3C or DIM at lower dose levels will not alter CYP-mediated metabolism of TAM, and hence, its theraputic efficacy.