醋酸環丙孕酮
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臨床資料 | |
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商品名 | Androcur、Cyprostat、Siterone、色普龍、安得卡等 |
AHFS/Drugs.com | Micromedex詳細消費者藥物資訊 |
懷孕分級 |
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給藥途徑 | 口服給藥, 肌肉注射 |
ATC碼 | |
法律規範狀態 | |
法律規範 |
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藥物動力學資料 | |
生物利用度 | 100% |
血漿蛋白結合率 | 96% |
藥物代謝 | 肝臟 |
生物半衰期 | 40小時 |
排泄途徑 | 60%膽,33%腎 |
識別資訊 | |
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CAS號 | 427-51-0 ![]() |
PubChem CID | |
IUPHAR/BPS | |
ChemSpider | |
UNII | |
ChEBI | |
ChEMBL | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.006.409 |
化學資訊 | |
化學式 | C24H29ClO4 |
莫耳質量 | 416.94 g/mol |
3D模型(JSmol) | |
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![]() | 此條目可參照英語維基百科相應條目來擴充。 |
醋酸環丙孕酮(cyproterone acetate,CPA),商品名有:色普龍、Androcur、安得卡等,是一種合成甾體抗雄激素、黃體製劑、抗促性腺激素。[1] 因其阻止內源雄激素與其受體結合以及抑制雄激素生物合成的抗雄作用,此藥主要用於雄激素相關病況的治療。[2] 有時也會使用CPA的孕激素樣作用,例如達英–35(英語:Diane-35)這種複合口服避孕藥就是此藥和炔雌醇復配而成。[3]
醫療用途
[編輯]CPA自1964年來就作為抗雄藥劑使用,且是第一個用於臨床的抗雄藥。[4]此藥在歐洲廣泛使用,在加拿大、墨西哥等國家亦有使用。 由於對肝毒性的擔憂,美國食品藥品監督管理局並未批准此藥,於是在美國使用醋酸甲羥孕酮取而代之。[5]CPA已被批准用於乳腺癌、 性早熟、與雄激素相關的皮膚病(如粉刺、脂溢性皮炎、雄激素性脫髮),以及降低性罪犯的性衝動。[6]CPA與炔雌醇複方(有時稱作co-cyprindiol)自1997年來也作為避孕藥出售。[4]
CPA的其他適應症有良性前列腺增生症、陰莖異常勃起、性慾亢進、性偏離、潮熱、女性雄激素過剩等。此外,CPA也廣泛用於跨性別女性的性別肯定激素治療(GAHT),美國由於未批准使用此藥,一般則會使用螺內酯,一種具有抗雄作用的利尿劑。[7]
觀察
[編輯]CPA可能對強迫症有效。[8]在非常有限的臨床研究報告中,CPA對女性強迫症「相當有效」。[9][10]
副作用
[編輯]女性化
[編輯]CPA的抗雄及抗促性腺激素作用在男性中直接造成的副作用有身體去雄性化、雌性化、乳房發育、乳房疼痛、乳溢症、性功能障礙(包括性慾減退和勃起功能障礙)、生精障礙和可逆轉的不育。[4]在前列腺癌治療中,CPA被男性患者稱為能造成如手術閹割一般「嚴重」的性慾和勃起功能減退。[11]
抑鬱
[編輯]現已發現CPA在男女中皆與抑鬱率升高相關。[12]有報告稱使用此藥治療多毛症(劑量25–100 mg)的女性中,可能有多達20–30%顯示抑鬱症狀。[13][14]同時,也有研究發現大約20%的服用Dianette牌口服避孕藥(只含2 mg CPA)的女性發生抑鬱。[15],和接受更具選擇性的GnRH類似物(一般不認為有顯著抑鬱風險,持續雌激素補充的話)治療的跨性別女性相比,使用CPA作為GAHT的抗雄成分的患者也有高得多的出現抑鬱症狀的風險,且此風險與CPA關聯。[16]CPA的抑鬱作用可能與其糖皮質素、抗雄激素、和/或抗促性腺激素作用有關,畢竟糖皮質素、抗雄激素(對男性來說)以及GnRH類似物都和抑鬱有關聯。[17][18][19][20]CPA造成的維生素B12缺乏症也有可能是一個很重要的因素。[15]由於抑鬱的副作用,在將CPA用於有抑鬱症病史的患者時應特別小心,特別是當抑鬱病史嚴重之時。[21]
血栓
[編輯]當單獨使用時,CPA對凝血因子並沒有表現出什麼顯著作用。然而在口服避孕藥之類的情況下與炔雌醇聯用時,便會提升發生深靜脈血栓的風險。[22]服用含有CPA的避孕藥的女性和不服用的女性相比,血栓形成的概率提升六到七倍,與服用含左炔諾孕酮避孕藥的女性比則為兩倍。[23]
肝毒性
[編輯]CPA的最嚴重的潛在副作用為其肝毒性。因此,服用CPA的患者,尤其是高劑量服用者(每日超過50–100 mg甚至200–300 mg),應該持續監視肝功能測試結果。[24]CPA的毒性取決於劑量,口服避孕藥中2 mg那麼低的劑量並沒有顯現出多少風險。[25]
腦膜瘤
[編輯]在罕見的情況下,高劑量(至少 25 mg/d)的CPA療法與腦膜瘤的發生及惡化有關。此現象未見於低劑量的避孕藥用途。[26][27]因此,腦膜瘤或腦膜瘤病史為使用CPA的一個禁忌。[21]
雜項
[編輯]聯合雌激素使用高劑量的CPA在跨性別女性中和強烈(高達400倍)的高催乳素血症有關。[28]對於同一群體,單獨雌激素則只與少數單一的催乳素瘤有關。[28]
由於對於雌激素生產的抑制,長期高劑量使用CPA而不伴隨雌激素可引發骨質酥鬆症,對兩性皆然。[29]
CPA也和妊娠紋生成有關,可能是由其糖皮質素活性和/或其造成的皮膚乾燥導致。[30]
現已發現高劑量(至少 50–100 mg/d)服用CPA會導致維生素B12缺乏症。[31][32] 在維生素B12缺乏症引發的多種症狀中,由於單胺類神經傳導物質耗盡引發的焦慮、應激性、疲倦較值得注意,[33][34]此外也有證據提示此症可能與CPA治療中常見的神經—精神(neuropsychiatric)不良反應有關。[15]因此,建議在大劑量CPA質量中監測血清維生素B12含量並適時補充。[31][32]
戒斷
[編輯]對CPA的突然戒斷可能有害。Schering AG的說明書建議逐步降低劑量,每隔幾周降低一次,每次減少的每日用量不超過50 mg。對戒斷主要的擔憂來自CPA對腎上腺的影響。由於其糖皮質素作用,高劑量的CPA可能會降低ACTH,從而在突然戒斷時導致腎上腺皮質功能不全。此外,CPA雖然降低性腺的雄激素分泌,卻能提升腎上腺的雄激素產生量,有時會甚至導致總體睪酮含量提升。[35]因此,突然停止使用CPA可能導致意外的雄激素效果。[來源請求]之所以有這個擔憂是因為雄激素(特別是二氫睪酮)抑制腎上腺功能,進一步降低皮質類固醇生成。[36]
腎上腺皮質功能不全
[編輯]有報道稱醋酸環丙孕酮治療中導致腎上腺功能抑制及促腎上腺皮質素(ACTH)回應減弱的報告。這會導致腎上腺皮質功能不全,從而在停藥時可能出現低皮質醇和醛固酮,以及較弱的ACTH反應。低醛固酮可能會導致低鈉血症和高鉀血症。服用醋酸環丙孕酮的患者應持續監測皮質醇和電解質情況,並在出現高鉀血症時降低高鉀含量食物的進食量,或是停止服藥。
抗雄戒斷症候群
[編輯]一些前列腺癌細胞會對醋酸環丙孕酮表現出一種截然不同的現象——這些細胞的雄激素受體發生突變,於是和平常情況下被醋酸環丙孕酮抑制不同,這些受體能被其活化。在這樣的病例中,停止服用醋酸環丙孕酮反而可能減緩癌症生長。[37]
藥理
[編輯]活性概要
[編輯]已知醋酸環丙孕酮存在以下藥理學活性:
- 雄激素受體(AR)受體拮抗劑/極弱部分促效劑[38]
- 孕酮受體(PR)促效劑(Kd = 15 nM; IC50 = 79 nM)[38][39]
- 糖皮質素受體(GR)拮抗劑(Kd = 45 nM; IC50 = 360 nM)[39]
- 21-羥化酶、3β-羥基類固醇去氫酶(3β-HSD)、17α-羥化酶、17,20-解離酶抑制劑[40]
- 孕烷 X 受體(PXR)促效劑(因而調控 CYP3A4、P-醣蛋白)[41][42]
醋酸環丙孕酮的孕激素和抗雄激素作用等強,[43]為17α-羥基黃體酮一族中最強的黃體激素。其強度為的醋酸羥孕酮的1200倍、醋酸甲羥孕酮的12倍、醋酸氯地孕酮的三倍。[43]17α-羥基黃體酮一族的孕激素極其強效,而醋酸環丙孕酮更是已知最強的孕激素,在生物檢定法中有1000倍於孕酮的強度。[44]還有文獻稱CPA是迄今為止「最強力的」抗雄激素。[44]
CPA也可能對5α還原酶有輕微的抑制作用,不過目前的證據是稀少而互相矛盾。[45][46][47]與非那雄胺(一種既定的5α還原酶抑制劑)合用時,CPA對脫髮的療效遠高於單用CPA時的情況——這提示要是CPA真的對5α還原酶有直接抑制作用,也不會多麼突出。[48][49]
CPA對雌激素受體(ER)或礦物皮質素受體(MR)沒有什麼親和力。[來源請求]
CPA還會非選擇性地和μ-、δ-、κ-阿片樣肽受體結合,不過與其其它活性相比弱得多—(抑制 [3H]二丙諾啡結合的 IC50 = 1.62 ± 0.33 µM)。[50]研究提示CPA活化阿片樣肽受體的能力也許可以解釋其高劑量下鎮靜的副作用,以及其治療叢集性頭痛的功能。[50]
抗雄活性
[編輯]醋酸環丙孕酮是一種較強的雄激素受體(AR)競爭性拮抗劑。[38]CPA可以直接阻礙內源性雄激素(如睪酮 (T)、雙氫睪酮 (DHT))結合、活化雄激素受體,從而阻止其在體內產生雄激素作用。然而和螺內酯一樣,醋酸環丙孕酮、醋酸氯地孕酮、醋酸甲羥孕酮這樣的甾體抗雄激素並非單純的雄激素受體拮抗劑,而是一種很弱的部分促效劑。[38][51][52][53]臨床上,醋酸環丙孕酮基本上只展現出其抗雄激素的一面——CPA在受體處替換掉本來可以與之結合的那些效能的雄激素(T、DHT等),因此其淨效應一般都是降低雄激素的生理活性。由於在雄激素受體處CPA仍有較弱的效能,CPA不能像氟他胺這樣的AR沉默拮抗劑完全去除雄激素活性,總是會在一定程度上維持這種活性。
醋酸環丙孕酮活化雄激素受體的能力儘管很弱,也還是足以在沒有其他雄激素的情況下促進對雄激素敏感的癌症——例如前列腺癌——生長(使用氟他胺一同治療可以防止)。[51][52]因此,醋酸環丙孕酮在治療這種癌症時可能不如非甾體抗雄藥中的某些沉默拮抗劑有效。除了氟他胺之外,比卡魯胺和恩雜魯胺也屬於AR沉默拮抗劑。[38][54]
間接雌激素活性
[編輯]由於CPA並不與雌激素受體(ER)結合,此藥基本不具備雌激素活性(無論直接還是間接),甚至可能因為其抗促性腺激素活性在劑量足夠時表現出抗雌作用。不過由於雄激素總體上會抵抗乳房雌激素的作用,單獨使用CPA可以在男性中通過抗雄激素活性造成類似於雌激素的乳房女性化效果。無論如何,醋酸環丙孕酮的這種副作用在發生率和嚴重程度上都遠低於非甾體抗雄藥的程度。非甾體抗雄藥不會降低(甚至會提高)雌激素水平。[55][56]
孕激素
[編輯]CPA是一種極強的孕激素;[57]之前也提到過, 其是目前已知最強效的孕激素。[44]與低劑量炔雌醇相結合作為激素避孕藥,每日只需2 mg醋酸環丙孕酮即可有效。[57][58]
由於其孕激素作用,醋酸環丙孕酮可以大幅增加催乳素分泌、誘導雌性普通獼猴乳腺發育。[59]相應地,研究表明CPA和雌激素配合長期用藥能使所有的跨性別女性的乳腺小葉完全發育。[60][61][62]在兩位實驗對象中觀察到了類似妊娠的乳腺增生。[62]同一個研究還發現男性攝護腺癌症患者在服用接受不帶孕激素活性的抗雄藥物且不服用雌激素時,其乳腺只會稍有不完全發育。[60]因此,上述研究的作者認為跨性別女性要得到類似女性的(包括乳腺小葉在內)完全發育的胸部的話,需要同時接受孕激素和雌激素作用。[60][61]同時研究者還注意到手術去勢後停止使用醋酸環丙孕酮會導致乳腺發育狀態還原,說明保持發育後的結構需要持續使用孕激素治療。[60]
醋酸環丙孕酮的孕激素作用致使其同時具有抗促性腺激素作用。[38][57]
抗促性腺激素
[編輯]CPA有強抗促性腺激素作用,[38]能夠抑制人類由促性腺激素釋放激素(GnRH)誘發分泌的促性腺激素過程,[63]因而顯著降低血漿中黃體成長激素(LH)和濾泡刺激素(FSH)的濃度。由此也使孕酮(P4)、雄烯二酮、睪酮、二氫睪酮、雌二醇(E2)濃度顯著降低;性激素結合球蛋白(SHBG)和催乳素含量則會上升。[64][65][66][67][68]CPA的抗促性腺激素活性由孕酮受體過活化誘發,[11][38][57]不過CPA的甾體酶抑制作用可能參與了其降低性類固醇水平的作用。[69]
其他活性
[編輯]糖皮質素
[編輯]由於下視丘-腦垂腺-腎上腺軸(HPA)的負反饋作用,施用強的松和地塞米松等外源性糖皮質素會抑制腦垂腺分泌促腎上腺皮質素,從而抑制腎上腺分泌皮質醇,導致腎上腺抑制和萎縮。此時停止施用糖皮質素會導致一過性的腎上腺功能不全。CPA同樣能夠稍微降低ACTH、皮質醇水平,誘發腎上腺萎縮,且在停藥後也會造成人類和動物腎上腺功能不全,說明其也具有一些糖皮質素作用。[70][71][72][73][74][75]矛盾的是,CPA在體外是糖皮質素受體(GR)拮抗劑,[39][76][77]且能夠通過抑制3β-羥基類固醇去氫酶和21-羥化酶抑制腎上腺生產皮質醇和皮質酮,[71][78][79][80]因而表現出抗糖皮質素活性。這個矛盾或許可以通過分析醋酸環丙孕酮的活性代謝產物解開:CPA的一些代謝產物,例如15β-羥基醋酸環丙孕酮(人類中的血清濃度為CPA原藥兩倍[81]),[82]是糖皮質素促效劑。[83]由此可以假設這些產物總體的糖皮質素活性蓋過了CPA本身的抗糖皮質素活性。環丙孕酮及其醋酸酯CPA通過各自的代謝產物都表現出糖皮質素活性。基於小鼠研究,CPA的糖皮質素活性強度大約為強的松的1/5。[84]
即使不少研究都顯示醋酸環丙孕酮會顯著造成皮質醇和ACTH相應降低,也有些研究報告即使劑量很高也沒有這種效果。[83][85][86][87][88]
醋酸甲地孕酮、醋酸甲羥孕酮、醋酸氯地孕酮、類固醇黃體素和醋酸環丙孕酮的一些結構似體都有類似地糖皮質素作用,因此都可能在停藥時造成腎上腺功能不全。[89][90]
藥物代謝
[編輯]CPA的親脂性使其藥物代謝動力學特性複雜許多。雖然對於CPA的平均生物半衰期一般估計為40小時左右,這個時長主要卻是反映其在脂肪細胞中的累積過程。從血液中清除CPA的過程相比起來快上很多;脂肪中的儲量可能受食物攝入影響。因此,建議按每日分2–3次,或者使用長效注射劑給藥。
一部分攝入體內的CPA通過水解,代謝為環丙孕酮和乙酸。[91]不過,和其他類固醇酯不同,CPA並不會被大量水解;其藥理活性實際上很多都來自於其原始形式:[24]醋酸環丙孕酮的抗雄活性大約為環丙孕酮三倍,[92]此外環丙孕酮本身完全不帶孕激素活性。[44]
CPA由CYP3A4代謝,生成活性代謝產物醋酸15β-羥基環丙孕酮。此產物保留了CPA的抗雄活性,孕激素活性則有下降。[81][93][94]因此,與抑制CYP3A4的藥物一同給藥可提升醋酸環丙孕酮的孕激素活性。
吸收
[編輯]醋酸環丙孕酮的口服生物利用率被報告為100%。[95]然而,有說法稱醋酸環丙孕酮通過消化道吸收較差,所以應該在進食後服用,能提升吸收效率。[96]
分布
[編輯]代謝
[編輯]排泄
[編輯]歷史
[編輯]CPA於1960年代早期發現;1962年,Schering AG員工魯道夫·維歇特和身在柏林的F·紐曼申請了一個「黃體激素製劑」的專利(美國專利第3,234,093號)。專利通過後一年的1966年,紐曼就發表了CPA在大鼠中抗雄作用的證據;此外還報告了CPA對腦有「有組織的效果」。[97]同年,瑞典隆德的一組研究人員發表研究,展示CPA對於雄性胎鼠有導致泌尿生殖系統畸形的能力。[98]從此,全世界都開始在動物實驗中使用CPA研究抗雄激素影響性分化的程度和方式。
在1970年對於醋酸環丙孕酮進行了最早的人類實驗——在口服給藥後測量血漿中的藥物濃度、精子生產速率[99],還有在女性中測量頭發生長速度。1972年,精神科醫師開始在「性變態」患者上使用這種藥物[100]。1970年代中葉,螺內酯這類的不帶或帶有較弱孕激素作用的抗雄藥開始出現。在亮丙瑞林開發出來之前,醋酸環丙孕酮是僅有的幾種治療性早熟的藥物。
社會與文化
[編輯]命名
[編輯]「cyproterone acetate」為醋酸環丙孕酮的INN、USAN、BAN、JAN命名。此物質也可稱為1,2α-亞甲基-6-氯-δ6-17α-乙醯氧基黃體酮。
醋酸環丙孕酮與炔雌醇的複方製劑的商品在全球大部分地方名為「黛麗安」(Diane-35),在英國名為 Dianette,在德國名為 Bella Hexal,在瑞典名為 Diane,在智利名為 Dixi-35。[3]
參見
[編輯]外部連結
[編輯]- 醋酸環丙孕酮(德國 Androcur)說明書 (頁面存檔備份,存於網際網路檔案館)
- 醋酸環丙孕酮(南非版 Androcur)說明書 (頁面存檔備份,存於網際網路檔案館)
- 醋酸環丙孕酮(台灣 Androcur)說明書 (頁面存檔備份,存於網際網路檔案館)
- 醋酸環丙孕酮(紐西蘭 Siterone)說明書 (頁面存檔備份,存於網際網路檔案館)
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