가미소요산의 2.5시간 간격 7일 반복 병용 투여가 tamoxifen의 약물동력학에 미치는 영향

강현구 ( Hyun-Gu Kang ),박수진 ( Soo-Jin Park ),최성훈 ( Seong-hun Choi ),구세광 ( Sae-kwang Ku ) 대구한의대학교 제한동의학술원 2021 東西醫學 Vol.46 No.1

Objectives : This study aims to elucidate the possible effects on the pharmacokinetics (PK) of tamoxifen after 7-day repeated oral co-administration of Gamisoyo-san (GMSYS) with 2.5 hr-intervals, as a process of the comprehensive and integrative medicine, combination therapy of tamoxifen with GMSYS to achieve synergic pharmacodynamics and reduce toxicity in breast cancer patients. Materials and methods : Two point five hrs after treatment of tamoxifen 50 mg/kg, GMSYS 100 mg/kg was administered, once a day for 7 days. In tamoxifen single treated rats, 50 mg/kg of tamoxifen was orally administered and 2.5 hrs after treatment, distilled water 5 ml/kg was orally administered, instead of GMSYS solutions. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of last 7th tamoxifen treatment, and plasma concentrations of tamoxifen were analyzed using liquid chromatographic and mass-spectroscopic system. PK of tamoxifen (Tmax, Cmax, AUC, ti/2 and MRT_inf) after co-administration of GMSYS 100 mg/kg and tamoxifen 50 mg/kg, was analysis as compared with tamoxifen single administered rats using noncompartmental PK data analyzer programs. Each tamoxifen or GMSYS was orally administered, in a volume of 5 m/kg, dissolved in distilled water, once a day for 7 days. Results : GMSYS did not influence on the plasma concentrations of tamoxifen as compared with tamoxifen single treated rats and accordingly, no significant changes on the pharmacokinetics profiles, Tmax, Cmax, AUC, t_1/2 and MRT_inf were observed as compared with tamoxifen single treated rats, when tamoxifen 50 mg/kg and GMSYS 100 mg/kg 2.5 hr-interval co-administered, once aday for 7 days. Conclusion : Based on the results, co-administration of GMSYS with 2.5 hr-intervals did not critically influenced on the absorption and excretion of tamoxifen, the oral bioavailability. Hence, 2.5 hr-interval co-administration is considered as suitable regime of GMSYS and tamoxifen to achieve synergic pharmacodynamics and reduce toxicity for breast cancer patients as comprehensive and integrative therapy, and further pharmacodynamic studies should be conducted along with tamoxifen and GMSYS 2.5 hr-interval co-administration.

Tamoxifen과 blue honeysuckle 복합제제의 7일간 반복 투여가 tamoxifen의 약물동력학에 미치는 영향 연구

장태우 ( Tae-woo Jang ),강수진 ( Su-jinkang ),구세광 ( Sae-kwangku ),최성훈 ( Seong-hunchoi ),이영준 ( Yong-joonlee ) 대구한의대학교 제한동의학술원 2020 東西醫學 Vol.45 No.1

Objectives : This study aims to evaluate the effects of co-administration of blue honeysuckle (BH) and tamoxifen on pharmacokinetics of tamoxifen after 7 days repeated administration, as a process of the comprehensive and integrative medicine. Materials and methods : After 7 day-repeated oral treatment of 4 mg/kg of tamoxifen or tamoxifen 0.4 mg/㎖ with BH 40, 20 and 10 mg/㎖ concentration mixed formulas, the plasma was collected at 30 min before administration, 30 min, 1, 2, 3.5, 4, 6, 8 and 24 hrs, respectively. Plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. PK parameters of tamoxifen (Tmax, Cmax, AUC, t_1/2and MRT_inf) were analysis as compared witht amoxifen administered rats using noncompartmental PK data analyzer programs. Results : Although no significant changes on the tamoxifen plasma concentrations and PK parameters were demonstrated after end of 7 day-repeated oral administration of mixed formulas consisted of tamoxifen and BH 40 or 10 mg/㎖ as compared to tamoxifen 0.4 mg/㎖ treated rats, seven day-repeated oral administration of tamoxifen and BH 20 mg/㎖ mixed formula induced significant increase of plasma tamoxifen concentrations from 30 min to 3.5 hrs after end of administration with significant increases of Cmax as compared with tamoxifen 0.4 mg/㎖ single formula treated rats, not in AUC_0-t, and AUC_0-inf, respectively. Conclusion : Based on the results of the present study, 7 day-repeated oral administration of tamoxifen and BH 40, 20 or 10 mg/㎖ mixed formulas did not significantly influenced on the overall the oral bioavailability of tamoxifen, somewhat differed from the results of our previous single oral administration study, in which single oral administration of tamoxifen 0.4 mg/㎖ and BH 10 mg/㎖ mixed formulation induced decreases of the oral bioavailability of tamoxifen, but not in tamoxifen 0.4 mg/㎖ and BH 40 or 20 mg/㎖ mixed formulas.

자궁세포 성장에 미치는 항에스트로젠제의 작용기전

이중빈(Jung Bin Lee),윤미정(Mi-chung Yoon),김창미(Chang-mee Kim),홍사석(Sa Suk Hong),유경자(Kyung-za Ryu) 대한약리학회 1990 대한약리학잡지 Vol.26 No.2

비스테로이드성 항에스트로젠제는 표적기관에서 estrogen 수용체와 상경적으로 결합하므로써 estrogen의 작용을 억제하는 것으로 알려져 있다. 비스테로이드성 항에스트로젠제는 대체로 triphenylethylene계로서 tamoxifen, clomiphene, LYl17018등이 있으며 표적기관에서 estrogen의 작용을 억제하기 때문에 estrogen과 관련된 질환을 치료하는데 이용되어 오고 있다. 본 연구에서는 생후 21-23일된 미성숙 흰쥐를 재료로 항에스트로젠제중 tamoxifen과 LY117018이 자궁세포 성장에 어떠한 영향을 미치며 어떠한 기전으로 estrogen의 작용을 길항하는지를 규명하고자, 항에스트로젠제가 estrogen작용의 중요 지포에 미치는 영향을 비교 관찰하여 다음과 같은 결과를 얻었다. Tamoxifen과 LY117018은 자궁세포에서 estrogen의 영향이 없는 경우에는 estrogen agonist로, estrogen작용하에서는 estrogen antagonist로서 작용하였다. Estrogen 작용의 여러 가지 지표에 대해 tamoxifen이 LY117018보다 agonistic effect는 더 컸으나, antagonistic effect는 LY117018이 더 큰 것으로 나타났다. Estrogen 수용체에 대한 결합능은 LY117018이 estradiol보다는 약간 낮았으나 용량에 비례하여 estrogen 수용체와 결합하였다. 그러나 tamoxifen은 estrogen 수용체에 대한 결합이 아주 낮았다. Estrogen 수용체에 대한 binding affinity는 estradiol(100%), LY117018(77%), tamoxifen(6.3%) 순으로 나타났다. 항에스트로젠제의 생체내 투여는 estrogen 존재 유무에 따라 estrogen 수용체 농도에 agonist 또는 antagonist로 작용하였다. 항에스트로젠제의 단독투여는 progesterone 수용체 생성을 증가시키나, estrogen에 의하여 유도된 progesterone 수용체 생성을 억제하였다. 이상의 결과로 보아, tamoxifen과 LY117018은 estrogen유무에 따라 흰쥐 자궁세포에서 estrogen antagonist로서 뿐만 아니라 agonist로서도 작용함을 알 수 있다. 그러나 estrogen수용체와의 결합능력이 아주 낮은 tamoxifen은, 용량에 비례하여 estrogen수용체에 결합하므로써 작용하는 LY117018과는 다른 기전으로 작용하는 것으로 생각된다. In the present study, we examined the effects of tamoxifen and LY117018 on various parameters for the estrogenic actions in order to understand the mechanism by which tamoxifen and LY117018 act on the uterine cells in 21-23 day old immature rats. Tamoxifen and LY117018 stimulated uterine weight and uterine contents of DNA, protein, and peroxidase activity in the absence of estradiol while inhibited above parameters in the presence of estradiol. Both cytosolic and nuclear progesterone receptors were increased by the treatment of tamoxifen and LY117018 as well as estradiol, but estradiol-induced increase in the progesterone receptors were reduced by the treatment of antiestrogens. These effects were enhanced by the multiple injections of antiestrogens. It seemed that tamoxifen was more agonistic than LY117018 but less antagonistic than LY117018, judged by their effects on various parameters for the estrogenic action. The affinities of estradiol, tamoxifen, and LY117018 for the estrogen receptor were 0.17 ± 0.01nM(100%), 1.10 ± 0.01nM(6.3%), and 0.23 ± 0.01nM(77%), respectively. Furthermore, LY117018 was the competitive ligand for the estrogen receptor in dose-related manner but tamoxifen was not. Following estradiol treatment, nuclear estrogen receptor was sharply increased by 1 h, reaching the maximum by 16 h, while tamoxifen and LY117018 slightly increased nuclear estrogen receptor by 1 h and then decreased thereafter. It is therefore concluded that LY117018 is a competitive antagonist for the estrogen receptor with less estrogenic activity, compared to tamoxifen with low affinity to the estrogen receptor, and tamoxifen may act through other binding site than the estrogen receptor.

Effect of Gamiondam-tang (GMODT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats

류은아,강수진,송창현,이봉효,최성훈,한창현,이영준,구세광 대한한의학회 2017 대한한의학회지 Vol.38 No.2

Objectives: The effects of Gamiondam-tang (GMODT) co-administration within 5min on the pharmacokinetics (PK) of tamoxifen were observed as a process of the comprehensive and integrative medicine, combination therapy of tamoxifen with GMODT to achieve synergic pharmacodynamics and reduce toxicity on the breast cancer. Methods: After 50mg/kg of tamoxifen treatment, GMODT 100mg/kg was administered within 5min. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMODT 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. Results: Co-administration with GMODT induced increased trends of plasma tamoxifen concentrations to 1hr after end of administration, and then showed decreased trends of plasma tamoxifen concentrations, and especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5hr after end of co-administration with GMODT and also related significant (p<0.05) decreases of AUC0-inf and MRTinf as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMODT 100 mg/kg within 5 min, in this experiment. Conclusion: Based on the results of the present study, it is considered that single co-administration GMODT within 5min significantly inhibited the oral bioavailability of tamoxifen through variable influences on the absorption and excretion of tamoxifen, can be influenced on the toxicity or pharmacodynamic of tamoxifen.

Effect of Gamiondam-tang (GMODT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats

Ryu, Eun-A,Kang, Su-Jin,Song, Chang-Hyun,Lee, Bong-Hyo,Choi, Seong-Hun,Han, Chang-Hyun,Lee, Young-Joon,Ku, Sae-Kwang The Society of Korean Medicine 2017 대한한의학회지 Vol.38 No.2

Objectives: The effects of Gamiondam-tang (GMODT) co-administration within 5min on the pharmacokinetics (PK) of tamoxifen were observed as a process of the comprehensive and integrative medicine, combination therapy of tamoxifen with GMODT to achieve synergic pharmacodynamics and reduce toxicity on the breast cancer. Methods: After 50mg/kg of tamoxifen treatment, GMODT 100mg/kg was administered within 5min. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of GMODT treatment, and plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. PK parameters of tamoxifen (Tmax, Cmax, AUC, $t_{1/2}$ and $MRT_{inf}$) were analysis as compared with tamoxifen single administered rats using noncompartmental pharmacokinetics data analyzer programs. Results: Co-administration with GMODT induced increased trends of plasma tamoxifen concentrations to 1hr after end of administration, and then showed decreased trends of plasma tamoxifen concentrations, and especially significant (p<0.05) increases of plasma tamoxifen concentrations were demonstrated at 0.5hr after end of co-administration with GMODT and also related significant (p<0.05) decreases of $AUC_{0-inf}$ and $MRT_{inf}$ as compared with tamoxifen single formula treated rats, at dosage levels of tamoxifen 10 mg/kg and GMODT 100 mg/kg within 5 min, in this experiment. Conclusion: Based on the results of the present study, it is considered that single co-administration GMODT within 5min significantly inhibited the oral bioavailability of tamoxifen through variable influences on the absorption and excretion of tamoxifen, can be influenced on the toxicity or pharmacodynamic of tamoxifen.

Effects of mixed formulation of tamoxifen and blue honeysuckle on the pharmacokinetics profiles of tamoxifen after single oral administration

Hu, Jin-Ryul,Jang, Tae-Woo,Kang, Su-Jin,Ku, Sae-Kwang,Choi, Seong-Hun,Lee, Young-Joon The Society of Korean Medicine 2019 대한한의학회지 Vol.40 No.4

Objectives: Here, we investigated the effects of concentrated and lyophilized powders Blue honeysuckle (BH) on the PK of tamoxifen, to establish the pharmacokinetics (PK) profiles as one of essential process in new drug development. Methods: After single oral treatment of 0.4 mg/ml of tamoxifen or tamoxifen 0.4 with BH 40, 20 and 10 mg/ml, the plasma were collected at 0.5 hr before administration, 0.5, 1, 2, 3, 4, 6, 8 and 24 hr after end of single or mixed formula treatment. Plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, t1/2 and MRTinf were analyzed using noncompartmental PK data analyzer programs. Results: Tamoxifen and BH 40 mg/ml did not induce any significant change on the plasma tamoxifen concentrations, while significant decreases were observed in tamoxifen and BH 10 mg/ml from 2 to 8 hr as compared with tamoxifen only, respectively. Furthermore, significant increases of Tmax in tamoxifen and BH 40 mg/ml, significant decreases of Cmax in tamoxifen and BH 20 mg/ml, significant decreases of AUC0-t, AUC0-inf and MRTinf in tamoxifen and BH 10 mg/ml were demonstrated as compared with tamoxifen only. Conclusion: Taken together, tamoxifen and BH 10 mg/ml induced significant decrease of the oral bioavailability of tamoxifen, while tamoxifen and BH 40 or 20 mg/ml did not critically influenced, suggesting formulated BH concentration-independencies. It, therefore, seems to be needed that pharmacokinetic study after repeated administration should be tested to conclude the effects of BH on the pharmacokinetics of tamoxifen.

Effects of mixed formulation of tamoxifen and blue honeysuckle on the pharmacokinetics profiles of tamoxifen after single oral administration

후진렬,장태우,강수진,구세광,최승훈,이영준 대한한의학회 2019 대한한의학회지 Vol.40 No.4

Objectives: Here, we investigated the effects of concentrated and lyophilized powders Blue honeysuckle (BH) on the PK of tamoxifen, to establish the pharmacokinetics (PK) profiles as one of essential process in new drug development. Methods: After single oral treatment of 0.4 mg/ml of tamoxifen or tamoxifen 0.4 with BH 40, 20 and 10 mg/ml, the plasma were collected at 0.5 hr before administration, 0.5, 1, 2, 3, 4, 6, 8 and 24 hr after end of single or mixed formula treatment. Plasma concentrations of tamoxifen were analyzed using LC-MS/MS methods. Tmax, Cmax, AUC, t1/2 and MRTinf were analyzed using noncompartmental PK data analyzer programs. Results: Tamoxifen and BH 40 mg/ml did not induce any significant change on the plasma tamoxifen concentrations, while significant decreases were observed in tamoxifen and BH 10 mg/ml from 2 to 8 hr as compared with tamoxifen only, respectively. Furthermore, significant increases of Tmax in tamoxifen and BH 40 mg/ml, significant decreases of Cmax in tamoxifen and BH 20 mg/ml, significant decreases of AUC0-t, AUC0-inf and MRTinf in tamoxifen and BH 10 mg/ml were demonstrated as compared with tamoxifen only. Conclusion: Taken together, tamoxifen and BH 10 mg/ml induced significant decrease of the oral bioavailability of tamoxifen, while tamoxifen and BH 40 or 20 mg/ml did not critically influenced, suggesting formulated BH concentration-independencies. It, therefore, seems to be needed that pharmacokinetic study after repeated administration should be tested to conclude the effects of BH on the pharmacokinetics of tamoxifen.

Effects of mixed formulation of tamoxifen and blue honeysuckle on the pharmacokinetics profiles of tamoxifen after single oral administration

Jin-Ryul Hu,Tae-Woo Jang,Su-Jin Kang,Sae-Kwang Ku,Seong-Hun Choi,Young-Joon Lee 대한한의학회 2019 대한한의학회지 Vol.40 No.4

Effect of Gamiondam-tang (GMODT), a Polyherbal Formula on the Pharmacokinetics Profiles of Tamoxifen in Male SD Rats

Eun-A Ryu,Su-Jin Kang,Chang-Hyun Song,Bong-Hyo Lee,Seong-Hun Choi,Chang-Hyun Han,Young-Joon Lee,Sae-Kwang Ku 대한한의학회 2017 대한한의학회지 Vol.38 No.2

Action Mechanism of Antiestrogens on Uterine Growth in Immature Rats

이중빈,윤미정,김창미,홍사석,유경자,Lee, Jung-Bin,Yoon, Mi-Chung,Kim, Chang-Mee,Hong, Sa-Suk,Ryu, Kyung-Za The Korean Society of Pharmacology 1990 대한약리학잡지 Vol.26 No.2

비스테로이드성 항에스트로젠제는 표적기관에서 estrogen 수용체와 상경적으로 결합하므로써 estrogen의 작용을 억제하는 것으로 알려져 있다. 비스테로이드성 항에스트로젠제는 대체로 triphenylethylene계로서 tamoxifen, clomiphene, LYl17018등이 있으며 표적기관에서 estrogen의 작용을 억제하기 때문에 estrogen과 관련된 질환을 치료하는데 이용되어 오고 있다. 본 연구에서는 생후 21-23일된 미성숙 흰쥐를 재료로 항에스트로젠제중 tamoxifen과 LY117018이 자궁세포 성장에 어떠한 영향을 미치며 어떠한 기전으로 estrogen의 작용을 길항하는지를 규명하고자, 항에스트로젠제가 estrogen작용의 중요 지포에 미치는 영향을 비교 관찰하여 다음과 같은 결과를 얻었다. Tamoxifen과 LY117018은 자궁세포에서 estrogen의 영향이 없는 경우에는 estrogen agonist로, estrogen작용하에서는 estrogen antagonist로서 작용하였다. Estrogen 작용의 여러 가지 지표에 대해 tamoxifen이 LY117018보다 agonistic effect는 더 컸으나, antagonistic effect는 LY117018이 더 큰 것으로 나타났다. Estrogen 수용체에 대한 결합능은 LY117018이 estradiol보다는 약간 낮았으나 용량에 비례하여 estrogen 수용체와 결합하였다. 그러나 tamoxifen은 estrogen 수용체에 대한 결합이 아주 낮았다. Estrogen 수용체에 대한 binding affinity는 estradiol(100%), LY117018(77%), tamoxifen(6.3%) 순으로 나타났다. 항에스트로젠제의 생체내 투여는 estrogen 존재 유무에 따라 estrogen 수용체 농도에 agonist 또는 antagonist로 작용하였다. 항에스트로젠제의 단독투여는 progesterone 수용체 생성을 증가시키나, estrogen에 의하여 유도된 progesterone 수용체 생성을 억제하였다. 이상의 결과로 보아, tamoxifen과 LY117018은 estrogen유무에 따라 흰쥐 자궁세포에서 estrogen antagonist로서 뿐만 아니라 agonist로서도 작용함을 알 수 있다. 그러나 estrogen수용체와의 결합능력이 아주 낮은 tamoxifen은, 용량에 비례하여 estrogen수용체에 결합하므로써 작용하는 LY117018과는 다른 기전으로 작용하는 것으로 생각된다. In the present study, we examined the effects of tamoxifen and LY117018 on various parameters for the estrogenic actions in order to understand the mechanism by which tamoxifen and LY117018 act on the uterine cells in 21-23 day old immature rats. Tamoxifen and LY117018 stimulated uterine weight and uterine contents of DNA, protein, and peroxidase activity in the absence of estradiol while inhibited above parameters in the presence of estradiol. Both cytosolic and nuclear progesterone receptors were increased by the treatment of tamoxifen and LY117018 as well as estradiol, but estradiol-induced increase in the progesterone receptors were reduced by the treatment of antiestrogens. These effects were enhanced by the multiple injections of antiestrogens. It seemed that tamoxifen was more agonistic than LY117018 but less antagonistic than LY117018, judged by their effects on various parameters for the estrogenic action. The affinities of estradiol, tamoxifen, and LY117018 for the estrogen receptor were $0.17{\pm}0.01nM(100%)$, $1.10{\pm}0.01nM(6.3%)$, and $0.23{\pm}0.01nM(77%)$, respectively. Furthermore, LY117018 was the competitive ligand for the estrogen receptor in dose-related manner but tamoxifen was not. Following estradiol treatment, nuclear estrogen receptor was sharply increased by 1 h, reaching the maximum by 16 h, while tamoxifen and LY117018 slightly increased nuclear estrogen receptor by 1 h and then decreased thereafter. It is therefore concluded that LY117018 is a competitive antagonist for the estrogen receptor with less estrogenic activity, compared to tamoxifen with low affinity to the estrogen receptor, and tamoxifen may act through other binding site than the estrogen receptor.