骨化三醇

骨化三醇
臨床資料
讀音	美國 /ˌkælsɪˈtraɪɒl/; ; 英國 /kælˈsɪtriɒl/
商品名（英語：Drug nomenclature）	Rocaltrol, Calcijex, Decostriol, others
其他名稱	1,25-dihydroxycholecalciferol, 1alpha,25-dihydroxyvitamin D3, 1,25-dihydroxyvitamin D3, 1α,25-(OH)2D3, 1,25(OH)2D
AHFS/Drugs.com	Monograph
MedlinePlus	a682335
核准狀況	美 DailyMed: Calcitriol;
懷孕分級	澳: B3 ; ;
給藥途徑	口服給藥, 靜脈注射
ATC碼	A11CC04 (WHO) D05AX03;
法律規範狀態
法律規範	澳：限醫生處方（S4）; 加：處方藥（℞-only）; 英：處方藥（℞-only） (POM); 美：處方藥（℞-only）;
藥物動力學資料
血漿蛋白結合率	99.9%
藥物代謝	腎臟
生物半衰期	5–8小時 (成人), 27小時 (兒童)
排泄途徑	糞便 (50%), 尿液 (16%)
識別資訊
	IUPAC命名法 (1R,3S)-5-[2-[(1R,3aR,7aS)-1-[(2R)-6-hydroxy-6-methyl-heptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H- inden-4-ylidene]ethylidene]-4-methylidene-cyclohexane-1,3-diol; ;
CAS號	32222-06-3
PubChem CID	5280453;
IUPHAR/BPS	2779;
DrugBank	DB00136 ;
ChemSpider	4444108 ;
UNII	FXC9231JVH;
KEGG	D00129;
ChEBI	CHEBI:17823 ;
ChEMBL	ChEMBL846 ;
PDB配體ID	VDX (PDBe, RCSB PDB);
CompTox Dashboard（英語：CompTox Chemicals Dashboard） (EPA)	DTXSID5022722 ;
ECHA InfoCard	100.046.315
化學資訊
化學式	C27H44O3
莫耳質量	416.65 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	SMILES C[C@H](CCCC(C)(C)O)[C@H]1CC[C@@H]\2[C@@]1(CCC/C2=C\C=C/3\C[C@H](C[C@@H](C3=C)O)O)C;
	InChI InChI=1S/C27H44O3/c1-18(8-6-14-26(3,4)30)23-12-13-24-20(9-7-15-27(23,24)5)10-11-21-16-22(28)17-25(29)19(21)2/h10-11,18,22-25,28-30H,2,6-9,12-17H2,1,3-5H3/b20-10+,21-11-/t18-,22-,23-,24+,25+,27-/m1/s1 ; Key:GMRQFYUYWCNGIN-NKMMMXOESA-N ;

骨化三醇（英語：Calcitriol，又稱為1,25-二羥膽鈣化醇或是1,25-二羥維生素D₃）是維生素D的活性形式，在正常的情況下由腎臟製造。它是一種激素，^[8]可結合並活化細胞核中的維生素D受體（英語：vitamin D receptor），而增加許多基因的表達。^[9]骨化三醇主要透過增加腸道對鈣的吸收來增加血液中的鈣質 (鈣離子，Ca²⁺)。^[7]在調節血鈣與血磷濃度方面有重要作用。

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生物合成

7-去氫膽固醇在皮膚內經紫外線的照射下生成膽鈣化醇（維生素D₃），後者在肝臟中經羥化酶系的作用下羥化為25-羥膽鈣化醇，繼而經血液被轉運到腎臟，腎臟近曲小管細胞中的CYP27B1（細胞色素 P450 27B1）將25-羥膽鈣化醇羥化為1,25-二羥膽鈣化醇。

當血液中維生素D、鈣、磷的含量下降時，1,25-二羥膽鈣化醇生成量會增加。副甲狀腺素會增加腎臟中CYP27B1的活性，使得1,25-二羥膽鈣化醇生成量增多，可協同副甲狀腺素增加血鈣。

生理作用

加速合成鈣結合蛋白，而使得腸道吸收鈣質。
促進腸道吸收磷。
同時增加破骨細胞與成骨細胞的數量，但對前者的效應要高於後者，故總體來說是增加血鈣。
增強腎小管對鈣和磷的重吸收，而減少尿液中鈣的流失。

故總體來說，骨化三醇可增加血液中鈣和磷的含量。

骨化三醇的作用原理很多情況下是通過與維生素D受體（VDR）結合，例如小腸上皮細胞細胞質中的受體與骨化三醇結合而成的配體-受體複合物轉移到到細胞核中作為促進鈣結合蛋白的編碼基因的表現的轉錄因子，鈣結合蛋白增加使細胞主動運輸更多的鈣離子，而提高鈣離子吸收水平。吸收鈣離子同時為維持電中性也需要運輸陰離子，主要是吸收無機磷酸根離子，所以骨化三醇也可促進磷的吸收。^[10]

醫療應用

骨化三醇被用於治療低血鈣症、副腎上腺功能減退症（成人）、骨質軟化，佝僂病（嬰幼兒）、慢性腎臟病、腎性骨病、骨質疏鬆症，預防糖皮質素引起的骨質疏鬆症。^[11]骨化三醇和其他維生素D受體-配體類似物在調節血鈣之外方面的應用也通過驗證。^[12]其口服劑用於治療乾癬^[13]和乾癬性關節炎。^[14]但對乾癬的療效證據尚不充分。^[15]維生素D類似物鈣泊三醇是比較常用的治療乾癬藥物。

副作用

骨化三醇可作為治療腎病變引起的低血鈣症和副甲狀腺功能亢進症、副甲狀腺功能昂進症引起的低血鈣症、骨質疏鬆症、骨質軟化症和家族性低磷血症（familial hypophosphatemia）。^[7]^[16]給藥方式為透過口服或是靜脈注射。^[7]過量使用會導致虛弱、頭痛、噁心、便秘、泌尿道感染和腹痛等副作用。^[7]^[16]嚴重的副作用有高血鈣和過敏性休克。^[7]建議個體在開始用藥和改變劑量之後要定期進行血液檢查。^[16]

相對於其他的維生素D化合物在臨床上的使用（膽鈣化醇，麥角鈣化醇），骨化三醇有更高誘導高血鈣症的風險。然而由於其相對短的生物半衰期，副作用也相對容易處理。^[11]

代謝

骨化三醇在體內的生物半衰期以小時為單位，而其前體骨化二醇的生物半衰期以週為單位。^[17]骨化三醇透過進一步羥基化形成1,24,25-三羥基維生素D、活性維生素 D3酸（英語：calcitroic acid）而失去活性。這是透過CYP24A1的作用而發生。^[18]活性維生素 D3酸更易溶於水，會隨膽汁和尿液排出。

歷史

骨化三醇於1971年首次由在美國教授Hector DeLuca（英語：Hector DeLuca）所主持實驗室中工作的麥克·H.·郝力克（英語：Michael F. Holick），另外還有安東尼·諾曼（英語：Anthony W. Norman）及其同事們^[19]^[20]所發現。^[21]

骨化三醇於1971年被確定為維生素D的活性形式，於1978年在美國被批准用作醫療用途。^[7]它有通用名藥物在市面販售。^[16]它是美國於2021年排名第258最常使用的處方藥，開立的處方箋數量超過100萬張。^[22]^[23]

此藥品已被列入世界衛生組織基本藥物標準清單之中。^[24]

社會與文化

骨化三醇有多種商品名，如Rocaltrol (羅氏藥廠)、Calcijex (亞培)、Decostriol (Mibe藥廠、Jesalis藥廠)、Vectical (Galderma藥廠（英語：Galderma）) 和 Rolsical (太陽製藥)。

參考資料

[1]
Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.
[2]
Wolters Kluwer, Stedman's Medical Dictionary, Wolters Kluwer.
[3]
Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.
[4]
Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt, [2015-09-25], （原始內容存檔於25 September 2015）.
[5]
Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster, [2015-09-25], （原始內容存檔於2020-05-25）.
[6]
IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981. European Journal of Biochemistry. May 1982, 124 (2): 223–227. PMID 7094913. doi:10.1111/j.1432-1033.1982.tb06581.x .
[7]
Calcitriol Monograph for Professionals. Drugs.com. American Society of Health-System Pharmacists. [9 April 2019] （英語）.
[8]
"Nomenclature of Vitamin D. Recomendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) （頁面存檔備份，存於網際網路檔案館）" reproduced at the Queen Mary University of London website. Retrieved 21 March 2010.
[9]
Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. The American Journal of Clinical Nutrition. August 2008, 88 (2): 491S–499S. PMID 18689389. doi:10.1093/ajcn/88.2.491S .
[10]
Voet, Donald; Voet, Judith G. (2004). Biochemistry. Volume one. Biomolecules, mechanisms of enzyme action, and metabolism, 3rd edition, pp. 663–664. New York: John Wiley & Sons. ISBN 0-471-25090-2.
[11]
Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
[12]
Sunil Nagpal, Songqing Na, Radhakrishnan Rathnachalam. Noncalcemic actions of vitamin D receptor ligands. Endocrine Reviews. 2005-8, 26 (5): 662–687 [2019-02-12]. ISSN 0163-769X. doi:10.1210/er.2004-0002. （原始內容存檔於2020-05-05）. 請檢查|date=中的日期值 (幫助).
[13]
Smith, Ellen L.; Pincus, Stephanie H.; Donovan, Lynne; Holick, Michael F. A novel approach for the evaluation and treatment of psoriasis. Journal of the American Academy of Dermatology (Elsevier BV). 1988, 19 (3): 516–528. ISSN 0190-9622. doi:10.1016/s0190-9622(88)70207-8.
[14]
Huckins, David; Felson, David T.; Holick, Michael. Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: a pilot study. Arthritis & Rheumatism (Wiley-Blackwell). 1990, 33 (11): 1723–1727. ISSN 0004-3591. doi:10.1002/art.1780331117.
[15]
Calcitriol. In: Klasco RK, editor. Drugdex system. vol 128. Greenwood Village (CO): Thomson Micromedex; 2006.
[16]
British national formulary : BNF 76 76. Pharmaceutical Press. 2018: 1050–1051. ISBN 9780857113382.
[17]
Brandi ML. Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes. Clinical Cases in Mineral and Bone Metabolism. September 2010, 7 (3): 243–250. PMC 3213838 . PMID 22460535.
[18]
Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. Journal of Lipid Research. January 2014, 55 (1): 13–31. PMC 3927478 . PMID 23564710. doi:10.1194/jlr.R031534 .
[19]
Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry. July 1971, 10 (14): 2799–2804. PMID 4326883. doi:10.1021/bi00790a023.
[20]
Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proceedings of the National Academy of Sciences of the United States of America. April 1971, 68 (4): 803–804. Bibcode:1971PNAS...68..803H. PMC 389047 . PMID 4323790. doi:10.1073/pnas.68.4.803 .
[21]
Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popják G. 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine. Science. July 1971, 173 (3991): 51–54. Bibcode:1971Sci...173...51N. PMID 4325863. S2CID 35236666. doi:10.1126/science.173.3991.51.
[22]
The Top 300 of 2021. ClinCalc. [2024-01-14]. （原始內容存檔於2024-01-15）.
[23]
Calcitriol - Drug Usage Statistics. ClinCalc. [2024-01-14].
[24]
World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. hdl:10665/345533 . WHO/MHP/HPS/EML/2021.02.

Template:Vitamin D receptor modulators

[Dorlands-1] [1]
Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.

[Stedmans-2] [2]
Wolters Kluwer, Stedman's Medical Dictionary, Wolters Kluwer.

[MW_Medical-3] [3]
Merriam-Webster, Merriam-Webster's Medical Dictionary, Merriam-Webster.

[AHD-4] [4]
Houghton Mifflin Harcourt, The American Heritage Dictionary of the English Language, Houghton Mifflin Harcourt, [2015-09-25], （原始內容存檔於25 September 2015）.

[MWU-5] [5]
Merriam-Webster, Merriam-Webster's Unabridged Dictionary, Merriam-Webster, [2015-09-25], （原始內容存檔於2020-05-25）.

[Nomen1981-6] [6]
IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN): Nomenclature of vitamin D. Recommendations 1981. European Journal of Biochemistry. May 1982, 124 (2): 223–227. PMID 7094913. doi:10.1111/j.1432-1033.1982.tb06581.x .

[AHFS2019-7] [7]
Calcitriol Monograph for Professionals. Drugs.com. American Society of Health-System Pharmacists. [9 April 2019] （英語）.

[8] [8]
"Nomenclature of Vitamin D. Recomendations 1981. IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) （頁面存檔備份，存於網際網路檔案館）" reproduced at the Queen Mary University of London website. Retrieved 21 March 2010.

[Norman_2008-9] [9]
Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. The American Journal of Clinical Nutrition. August 2008, 88 (2): 491S–499S. PMID 18689389. doi:10.1093/ajcn/88.2.491S .

[Voet-10] [10]
Voet, Donald; Voet, Judith G. (2004). Biochemistry. Volume one. Biomolecules, mechanisms of enzyme action, and metabolism, 3rd edition, pp. 663–664. New York: John Wiley & Sons. ISBN 0-471-25090-2.

[AMH2006-11] [11]
Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3

[12] [12]
Sunil Nagpal, Songqing Na, Radhakrishnan Rathnachalam. Noncalcemic actions of vitamin D receptor ligands. Endocrine Reviews. 2005-8, 26 (5): 662–687 [2019-02-12]. ISSN 0163-769X. doi:10.1210/er.2004-0002. （原始內容存檔於2020-05-05）. 請檢查|date=中的日期值 (幫助).

[13] [13]
Smith, Ellen L.; Pincus, Stephanie H.; Donovan, Lynne; Holick, Michael F. A novel approach for the evaluation and treatment of psoriasis. Journal of the American Academy of Dermatology (Elsevier BV). 1988, 19 (3): 516–528. ISSN 0190-9622. doi:10.1016/s0190-9622(88)70207-8.

[14] [14]
Huckins, David; Felson, David T.; Holick, Michael. Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: a pilot study. Arthritis & Rheumatism (Wiley-Blackwell). 1990, 33 (11): 1723–1727. ISSN 0004-3591. doi:10.1002/art.1780331117.

[MicromedexDrugdex-15] [15]
Calcitriol. In: Klasco RK, editor. Drugdex system. vol 128. Greenwood Village (CO): Thomson Micromedex; 2006.

[BNF76-16] [16]
British national formulary : BNF 76 76. Pharmaceutical Press. 2018: 1050–1051. ISBN 9780857113382.

[17] [17]
Brandi ML. Indications on the use of vitamin D and vitamin D metabolites in clinical phenotypes. Clinical Cases in Mineral and Bone Metabolism. September 2010, 7 (3): 243–250. PMC 3213838 . PMID 22460535.

[18] [18]
Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. Journal of Lipid Research. January 2014, 55 (1): 13–31. PMC 3927478 . PMID 23564710. doi:10.1194/jlr.R031534 .

[19] [19]
Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry. July 1971, 10 (14): 2799–2804. PMID 4326883. doi:10.1021/bi00790a023.

[pmid4323790-20] [20]
Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proceedings of the National Academy of Sciences of the United States of America. April 1971, 68 (4): 803–804. Bibcode:1971PNAS...68..803H. PMC 389047 . PMID 4323790. doi:10.1073/pnas.68.4.803 .

[pmid4325863-21] [21]
Norman AW, Myrtle JF, Midgett RJ, Nowicki HG, Williams V, Popják G. 1,25-dihydroxycholecalciferol: identification of the proposed active form of vitamin D3 in the intestine. Science. July 1971, 173 (3991): 51–54. Bibcode:1971Sci...173...51N. PMID 4325863. S2CID 35236666. doi:10.1126/science.173.3991.51.

[22] [22]
The Top 300 of 2021. ClinCalc. [2024-01-14]. （原始內容存檔於2024-01-15）.

[23] [23]
Calcitriol - Drug Usage Statistics. ClinCalc. [2024-01-14].

[WHO22nd-24] [24]
World Health Organization. World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. hdl:10665/345533 . WHO/MHP/HPS/EML/2021.02.

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