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Tamoxifen (Nolvadex^TM) is a nonsteroidal estrogen agonist-antagonist antineoplastic agent has been used for breast cancer¹⁾. It is the usual endocrine (anti-estrogen) therapy for hormone receptor-positive breast cancer in pre-menopausal women, and is also a standard in post-menopausal women although aromatase inhibitors are also frequently used in that setting²⁾. In addition, tamoxifen also used to treat infertility in women with anovulatory disorders³⁾ and prevention for gynecomastia⁴⁾. Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal⁵⁾. However, various side effects related to tamoxifen treatment also have been arise as bone loss in premenopausal women who continue to menstruate after adjuvant chemotherapy⁶⁾, endometrial changes, including cancer, are among tamoxifen's side effects⁷⁾, increased risk of thromboembolism⁸⁾, cause of fatty liver⁹⁾, reduced cognition ¹⁰⁾, semantic memory scores¹¹⁾ and libido¹²⁾, and premature growth plate fusion¹³⁾. Tamoxifen also depress the immune response¹⁴⁾, and it also known that hypersensitivity to tamoxifen or any ingredient in the formulation¹⁵⁾. Tamoxifen is contraindicated, when used in women with ductal carcinoma in situ and women at high risk for breast cancer, concurrent anticoagulant therapy with a warfarin derivative¹⁶⁾, and should be used with caution in patients with leukopenia or thrombocytopenia¹⁷⁾ and pregnant¹⁸⁾.

Gamisoyo-san (GMSYS; Jiawei-xiao-yao-san in Chinese, Kamishoyo-san in Japanese), one of the commonly prescribed herbal formulas consisted of 10 herbs – Angelicae Gigantis Radix, Paeoniae Radix, Atractylodis Rhizoma Alba, Hoelen, Bupleuri Radix, Gardeniae Fructus, Glycyrrhizae Radix et Rhizoma, Moutan Cortex, Menthae Herba and Zingiberis Rhizoma, has routinely been prescribed to relieve irregularity of menstruation, anxiety associated with the menstrual cycle and various menopause-related symptoms occurring in climacteric disturbance¹⁹⁾, Thus, it seems reasonable to suggest that GMSYS should be considered an alternative to hormone-replacement-therapy for patients with climacteric symptoms, especially those who presented psychological symptoms²⁰⁾. It is often prescribed for women who complain of general fatigue, hot flushes, stiff shoulders, insomnia, diaphoresis, depression, irritability, etc. It is also applied to treat diverse diseases, including autonomic imbalance, neurosis, eruption, chloasma (melasma), alopecia, constipation²¹⁾, functional dyspepsia²²⁾, Parkinson's disease and convulsions²³⁾, and breast cancer²⁴⁾. Although many researchers have investigated the pharmacological effects of GMSYS, there has been no study on its possible drug-drug interactions with tamoxifen.

In the present study, the effects of GMSYS co-administration on the pharmacokinetics of tamoxifen were observed as a process of the comprehensive and integrative medicine, combination therapy of tamoxifen with GMSYS to achieve synergic pharmacodynamics and reduce toxicity on the breast cancer patients. After 50 mg/kg of tamoxifen treatment, GMSYS 100 mg/kg was co-administered within 5 min. The plasma were collected at 30min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMSYS treatment, and plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. PK parameters of tamoxifen (Tmax, Cmax, AUC, t1/2 and MRTinf) were analysis as compared with tamoxifen single administered rats using noncompartmental pharmacokinetics data analyzer programs.

In the present study, the effects of GMSYS co-administration on the pharmacokinetics of tamoxifen were observed, combination therapy of tamoxifen with GMSYS to achieve synergic pharmacodynamics and reduce toxicity on the breast cancer patient. Although co-administration with GMSYS did not critically influenced on the pharmacokinetic parameters of oral tamoxifen, they induced increased trends of plasma tamoxifen concentrations, especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5 hr after end of co-administration with GMSYS as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 50 mg/kg and GMSYS 100 mg/kg within 5 min, in this experiment. These findings are considered as direct evidences that the adverse effects of tamoxifen could be influenced by the enhanced bioavailability of tamoxifen, which might be attributable to the promotion of absorption of tamoxifen by GMSYS. Hence, it is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration, about 2.5 hr-intervals, to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration, as a process of the comprehensive and integrative medicine, the combination therapy of tamoxifen with GMSYS on the breast cancer.

Tamoxifen was absorbed slowly following oral administration and Tmax of tamoxifen occur about 3-6 hrs after a single dose²⁷⁾ but it rapidly and extensively metabolized in the liver, through a substrate of CYP3A, 2C9, 2D6 including an active major metabolite, N-desmethyltamoxifen has biologic activity similar to that of the parent drug²⁸⁾. Steady-state concentrations of tamoxifen are attained after 3-4 weeks and those of N-desmethyltamoxifen, an active metabolite, are attained after 3-8 weeks²⁹⁾. Tamoxifen excreted principally in feces as polar conjugates³⁰⁾ with about 5-7 days of t1/2 in tamoxifen and 9-14 days in N-desmethyltamoxifen²⁷⁾. Clearance of tamoxifen is higher in female children 2-10 years of age than in women³¹⁾. In the present study, Tmax of tamoxifen in tamoxifen single oral treated rats was detected as 2.20±1.10 hr, and Cmax, AUC_0-t, AUC_0-inf, t_1/2 and MRT_inf were detected as 0.96±0.19 μg, 10.16±1.52 hr·μg/ml, 13.40±2.51 hr·μg/ml, 12.92±11.13 hr and 17.69±15.26 hr, respectively. In tamoxifen with GMSYS co-administered rats, Tmax, Cmax, AUC_0-t, AUC_0-inf, t_1/2 and MRT_inf of tamoxifen were detected as 2.40±1.14 hr, 1.00±0.21 μg, 10.70±1.98 hr·μg/ml, 12.70±2.75 hr·μg/ml, 9.21 ±1.30 hr and 12.03±1.47 hr as changed as 9.09, 4.25, 5.34, -5.21, -28.75 and -32.00% as compared with tamoxifen 50 mg/kg single oral treated rats, respectively. However, no significant changes on the pharmacokinetic parameters of oral tamoxifen were observed after single co-administration with GMSYS as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 50 mg/kg and GMSYS 100 mg/kg within 5 min, in this experiment.

As results of combination therapies with other drugs to improve the side effects of tamoxifen or to achieve synergic effects, various drug-drug interactions of tamoxifen have been evaluated; Because tamoxifen was metabolized by a substrate of CYP3A, 2C9, 2D6³²⁾, it interacted with various drugs, namely, combinations containing any of the following medications, depending on the amount present, may also interact with aminoglutethimide – decreased plasma tamoxifen and N-desmethyltamoxifen concentrations³³⁾, anticoagulants - enhanced warfarin effects³⁴⁾, bromocriptine – increased plasma tamoxifen and N-desmethyltamoxifen concentrations³⁵⁾, letrozole – decreased plasma letrozole concentrationsa³⁶⁾, medroxyprogesterone – decreased plasma N-desmethyltamoxifen concentrations but did not reduce plasma tamoxifen concentrations³⁷⁾, phenobarbital – decreased plasma tamoxifen concentrations³⁸⁾, rifampin – decreased plasma tamoxifen and N-desmethyltamoxifen concentrations³⁹⁾, and cyclosporine, erythromycin, diltiazem, erythromycin and nifedipine – competitively inhibited formation of N-desmethyltamoxifen in vitro⁴⁰⁾, respectively. However, interactions with herbal products have not been established except for some restricted natural compounds; tamoxifen enhanced warfarin effects, and it is contraindicate that co-administration of tamoxifen and wafarin³⁴⁾. In addition, we have been observed the possible interactions with Korean traditional polyherbal formulas; we observed that oral co-administration of Jaeumkanghwa-tang, a traditional yin-tonifying herbal medicine has been used for various oriental obstetrical and gynecological fields within 5min did not critically influenced on the pharmacokinetics profiles of tamoxifen after single⁴¹⁾ and repeated⁴²⁾ co-administration at dosage levels of 50 mg/kg in tamoxifen and 100 mg/kg in Jaeumkanghwa-tang, respectively. In this study, single co-administration of GMSYS with tamoxifen within 5min significantly increased the oral absorption of tamoxifen, enough to influence on the toxicity of tamoxifen. Hence, it is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration, about 2.5hr-intervals, to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration, as a process of the comprehensive and integrative medicine, the combination therapy of tamoxifen with GMSYS on the breast cancer.

Although single co-administration with GMSYS within 5 min did not influenced on the pharmacokinetic parameters of oral tamoxifen, GMSYS significantly increased the oral absorption of tamoxifen, when they were single co-administered within 5 min. Therefore, it is considered that pharmacokinetic studies should be tested like the effects of GMSYS on the pharmacokinetics of tamoxifen, when they were co-administered with prolonger intervals than Tmax of tamoxifen oral administration (about 2.5 hr-intervals), to achieve the optimal dosing regimen of GMSYS and tamoxifen co-administration, as a process of the comprehensive and integrative medicine, the combination therapy of tamoxifen with GMSYS on the breast cancer.