만성 간염에 있어서 한약의 약동학적 분석 논문

의사와 한의사, 의대생과 한의대생 사이의 대립이 심화되고 있다.

그 중에 한약은 깜장물 아니냐 뭐가 들어있는지도 모르는데 왜 쓰냐라는

이야기는 맨날 듣는 주제라 그러려니 해도

지금 시점에서 진짜로 믿는 사람들이 있는 것 같아 폄훼를 풀어보고자 매일 글을 쓰고 있다.

반응이 좋은 것 같아 글을 쓰는데 힘이 난다.

적극적으로 의견을 제시해주시는 분들도 계셔서 더욱 참고하고 있다.

이번 편은 특별히 한약의 약력학적 약동학적 분석을 요청하신 분이 계셔서 글을 쓴다.

이걸 검색하다가 in silico 에 대한 것도 같이 나왔는데

그건 차후에 다시 다루기로 한다. 이미 전체적으로 한약은 in silico로 진행되고 있음을 확인하였다.

(첨부파일 확인)

오늘은 다소 누군가에게는 거북할 수도 있는 주제이다.

네이버에 한약 약동학 약력학 이런 식으로 검색하면 나오는 블로그에 올라와 있는 논문을

찾아서 필요한 것만 요약해보았다.

출처 : https://www.blog.naver.com/beanalogue/221130843592

주제는 무려 만성 간염이다.

간 치료에 한약을 쓴다고 하면 편견을 가지고 보실 분들이 많지만

간에는 한약 이런 뜻은 아니고 쓸 수 있는 경우가 있다.

이번 논문은 그런 걸 이야기 하자는 것이기도 하지만 약동학적 분석만 알아보고자 한다.

Pharmacokinetic interactions of herbal medicines for the treatment of chronic hepatitis

Tun-PinHsueh^abWan-LingLin^cTung-HuTsai^ade

Journal of Food and Drug Analysis

Volume 25, Issue 2, April 2017, Pages 209-218

AUC; area under plasma concentration-time curve, 혈장농도곡선하 면적

Cmax: maximum plasma concentration, 최고혈장농도

Tmax: time to maximum plasma concentration, 최고혈장농도 도달시간

t1/2: elimination half-life, 소실 반감기

CL/F: clearance, 청소율

V/F: volume of distribution, 분포용적

F: bioavailability, 생체이용률

[출처] 임상시험 수행을 위한 약동학의 이해 |작성자 비타민B

약동학 지식은 일단 용어만 정리해보고 가자.

4. Pharmacokinetics of herbal medicines used for chronic hepatitis

4.1. Long-Dan-Xie-Gan-Tang (용담사간탕)

LDXGT treatment is used for acute or chronic hepatitis and accounts for 23.5% of the herbal formula presc/2ions for chronic hepatitis in Taiwan. The anti-inflammatory and antiherpetic virus effects of LDXGT have been reported previously . These properties contribute to the herbal medicines contained in this formula, which exhibit antihepatitis B and C virus effects, other antiviral effects (S. baicalensis, Glycyrrhiza uralensis, and G. scabra), anti-inflammatory effects (B. chinense, G. scabra, and G. jasminoides)  and antioxidation effects (B. chinense). G. scabra treatment may reverse hepatic fibrosis. 

The active compounds isolated from the LDXGT formula include gentiopicroside and swertiamarin, which are derived from G. scabra. Geniposide is isolated from G. jasminoides, and baicalin is derived from S. baicalensis. A pharmacokinetic study in freely moving rats after the oral administration of 10 g/kg LDXGT revealed that baicalin was absorbed rapidly and exhibited sustained levels among all of the notable compounds in LDXGT, with a t_max of 15.8 ± 9.0 minutes and t_1/2 of 314 ± 56.3 minutes in the concentration–time curve in plasma. The bimodal phenomenon of baicalin represented variable gastric emptying, enterohepatic recycling, or different absorption sites along gastrointestinal segments. Baicalin isolated from S. baicalensis also exhibited the longest elimination time of all compounds. Gentiopicroside and swertiamarin are derived from Gentiana species. Swertiamarin exhibited the least prolonged t_max at 97.5 ± 14.4 minutes and the lowest AUC (2.5 ± 0.1 min μg/mL), which indicated a rapid metabolization or biotransformation of this compound. Gentiopicroside showed the highest C_max (5767 ± 412 ng/mL) and the highest AUC, which were significantly different from those of other active compounds. Gentiopicroside is protective against hepatitis and exhibits free-radical-scavenging activity. These desc/2ive phenomena confirmed the role of the medicinal G. scabra and may explain the protective and immunological effects of LDXGT for hepatic disease.

4.2. Jia-Wei-Xiao-Yao-San (가미소요산)

The only pharmacokinetic study of JWXYS was performed on puerarin, which is derived from Radix Paeoniae Alba. Puerarin exhibited a mean absorption time to C_max of 51 minutes after oral administration of 5 g/kg medicinal powder to 11 individuals (6 functional dyspepsia patients and 5 healthy volunteers). The study revealed alternative pharmacokinetic variations of JWXYS between the two different patient conditions, but it did not clarify the full therapeutic picture of this formula because only a single component was analyzed.

4.3. XCHT (Sho-saiko-to) (소시호탕)

Pharmacokinetic analyses of baicalin and wogonoside isolated from Radix scutellariae after oral administration of 2 mL/100 g XCHT (which contained 265.4 mg/kg of baicalin and 58.78 mg/kg of wogonoside) to Sprague–Dawley rats demonstrated that these isolates exhibited double-peak phenomenon that was likely the result of enterohepatic circulation. The t_max 1 and t_max 2 of baicalin in XCHT was 7.8 ± 2.8 minutes and 384 ± 100.2 minutes, respectively. The t_max 1 and t_max 2 of wogonoside was 12.6 ± 12 minutes and 336 ± 100.2 minutes, respectively. The half-life of baicalin and wogonoside in XCHT was 3.6 hours and 4.9 hours, respectively. The pharmacokinetic parameters of baicalin and wogonoside support the notion that XCHT has a rapid onset and sustained effect during treatment. However, baicalin and wogonoside were derived from the same herbal medicine, and different compounds from various herbs in XCHT should be investigated to further reveal the pharmacokinetic properties of XCHT.

4.4. Yin-Chen-Hao-Tang (인진호탕)

The pharmacokinetic profiles of YCHT demonstrated that the t_max was approximately 35 minutes via measurement of the compound 6,7-dimethylesculetin, which is derived from A. capillaris, after oral administration of YCHT containing 12.0 mg/kg of 6,7-dimethylesculetin or 35.5 mg/kg of geniposide. The pharmacokinetic parameters of geniposide isolated from G. jasminoides demonstrated that the C_max and t_max were 11.54 ± 2.73 μg/mL and 16.2 ± 3.6 minutes, respectively. Another pharmacokinetic study of YCHT reached the same conclusion of a synergistic effect of the combination of these three herbs, and YCHT exhibited an increased plasma level and delayed elimination rate of 6,7-dimethylesculetin compared to the other one or two individual herbs combined. These studies lacked a validated internal standard compound, but the interaction of active compounds within the same formula could alter the therapeutic effectiveness of traditional herbal formulas.

5. Pharmacokinetic interaction of herbal medicines with Western drugs for chronic liver disease

5.1. LDXGT coupled with lamivudine

One potential drug interaction in patients with chronic hepatitis stems from lamivudine, which is a nucleoside analog and reverse transc/2ase inhibitor that is used to treat patients with hepatitis B virus infection. 

5.2. JWXYS coupled with 5-fluorouracil or etizolam

One study used multiple microdialysis probes to monitor the interaction of JWXYS and 5-fluorouracil (5-FU) in rat plasma and brain. The results revealed that JWXYS did not alter the AUC or C_max of 5-FU in plasma or brain, but it did increase the elimination half-life in the blood and brain at a dose of 2.4 g/kg/d orally, which corresponded to the maximum doses of 23.4 g/d for a 60-kg person. This maximum dose of JWXYS also increased the volume distribution in the blood and reduced clearance in the brain.

A possible leading cause of increased t_1/2 and clearance reduction is that JWXYS, which contains sufficient concentrations of flavonoids, 18-β-glycyrrhetic, acid or other compounds, inhibited the removal of 5-FU by P-glycoprotein in the brain. The suppressive effect of JWXYS on CYP1A2 __EXPRESSION__ at a high dose reduced the metabolic efficiency of 5-FU, which provides an additional explanation of the increase in t_1/2 and the volume of distribution.

5.3. XCHT and carbamazepine

An in vivo study orally administered the Kampo medicine Sho-saiko-to (XCHT) to rats for 2 weeks followed by treatment with carbamazepine (CBZ), which is a substrate of P450 and an anti-epilepsy drug. The results revealed no alternative pharmacokinetic parameters of CBZ or its toxic metabolite carbamazepine-10, 11-epoxide (CBZ-E). However, simultaneous oral administration up to 1 g/kg of XCHT in rats significantly decreased the C_max of CBZ and the AUC of CBZ-E. These phenomena may result from gastric emptying induced by XCHT and the slowed absorption of CBZ. XCHT is applicable in patients receiving CBZ because no interference was noted in the metabolism of CBZ, which is metabolized by CYP3A4.

출처의 요약을 그대로 인용하겠다.

1. 대만 National Health Insurance Research Database에 따르면 용담사간탕, 가미소요산, 소시호탕이 한의사에게 있어 만성 간염에 가장 자주 사용한 처방이었다.

2. 용담사간탕+lamivudine, 가미소요산+5-fluorouracil or etizolam, 소시호탕+carbamazepine 조합에서는 공동 투여시 약동학적 파라메터에 유의한 변화가 관찰되지 않았다.

3. 하지만 가미소요산은 혈액과 뇌에서 5-fluorouracil의 elimination t1.2를 지연시키고, 뇌에서는 clearance를 감소시켰으며, 소시호탕은 carbamazepine의 최대 농도와 대사산물의 생체 이용률을 감소시켰다.

이 논문 말고도 다른 약재 및 한약이 한국에서 진행된 논문도 있다.

상호작용에 관한 논문은 의과대학에서 연구한 논문도 있다. 

검색하면 나오며, 단일 약재의 경우 인삼이 가장 연구가 잘 되어있는 듯하다.

영어로 검색하면 여러 논문이 나오는데 대부분 중국 논문이었음.

본인 세 줄 요약

1. 한약의 약동학, 약력학적 분석은 이미 어느 정도 다 분석되어 있다. 다만, 중국어로.

2. 한약의 약동학, 약력학적 분석의 한국 연구는 진행중이며 실제 한약제제 등록 시에는 약동학 보고서를 제출해야 한다. (2015년부터 개정된 사항. 첨부파일 확인.)

3, 한약과 양약의 상호작용 연구는 한국, 중국, 대만 모두 부족한 상황이나 진행되고 있음.

이전 편들

1편 - 한약재 성분 알아보자 (1) 대황

https://orbi.kr/00031865004

2편 - 한약재 성분 알아보자 (2) 음양곽, 천궁

https://www.orbi.kr/00031889142

3편 - 한약재 성분 알아보자 (3) 황금, 단삼

https://www.orbi.kr/00031893262