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Ketoconazole is a synthetic imidazole antifungal drug used primarily to treat fungal infections. Ketoconazole is sold commercially as a tablet for oral administration (although this use has been discontinued in a number of countries), and in a variety of formulations for topical administration, such as creams (used to treat tinea; cutaneous candidiasis, including candidal paronychia; and pityriasis versicolor) and shampoos (used primarily to treat dandruff—seborrhoeic dermatitis of the scalp).^[6]

The less toxic and generally more effective triazole antifungal agents fluconazole and itraconazole are usually preferred for systemic use. In 2013 the European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) recommended that a ban be imposed on the use of oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits.^[7] The oral formulation of ketoconazole was discontinued in Australia in 2013^[8]^[9] and in China in 2015.^[10]

1 Medical uses
- 1.1 Antifungal
  - 1.1.1 Topical antifungal
  - 1.1.2 Systemic antifungal
- 1.2 Antiandrogen and antiglucocorticoid
- 1.3 Off-label uses
  - 1.3.1 Hair loss
- 1.4 Veterinary use
2 Side effects
3 Pharmacology
- 3.1 Resistance
4 Pharmacokinetics
5 History
6 Society and culture
- 6.1 Name
7 See also
8 References
9 Further reading
10 External links

Medical uses

Antifungal

Topical antifungal

Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor.^[11] Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin.^[11]^[12]^[13]

Systemic antifungal

Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus).^[14] First synthesized in 1977,^[11] ketoconazole was the first orally-active azole antifungal medication.^[14] However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.^[14]^[15]

Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.^[16]

Antiandrogen and antiglucocorticoid

The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol.^[14]^[16] Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase,^[16] which convert pregnenolone into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol.^[17] All of these enzymes are mitochondrial cytochrome p450 enzymes.^[18] Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer^[16]^[19] and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome.^[20] However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency.^[16] Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty.^[16] In any case, the risk of hepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.^[16]

Off-label uses

Hair loss

Nizoral (ketoconazole) 2% shampoo

Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor has been used off label to treat androgenic alopecia. The antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.^[21]

Limited clinical studies suggest ketoconazole shampoo used either alone^[22]^[23] or in combination with other treatments^[24] may be useful in reducing hair loss.

At least one study has been performed showing that ketoconazole may be useful in temporarily reducing erectile function in postoperative penile surgery patients.^[25]

Veterinary use

Ketoconazole is also sometimes prescribed by veterinarians for use on pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.^[26]

Side effects

Ketoconazole is a pregnancy category C drug because animal testing has shown it to cause teratogenesis when administered in high doses. Recently, the administration of systemic ketoconazole to two pregnant women for treatment of Cushing's syndrome was reported to have no adverse effects,^[27]^[28] but this small sample precludes drawing any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.^[29]

On July 2013, the U.S. Food and Drug Administration (FDA) issued a warning that taking ketoconazole orally can cause severe liver injuries and adrenal gland problems. It recommends Nizoral oral tablets should not be a first-line treatment for any fungal infection. Nizoral should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.^[30]

The topical formulations of Nizoral have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.^[30]

Pharmacology

As an antifungal, ketoconazole is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (CYP51A1).^[18] This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole and itraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greater affinity for fungal cell membranes.

As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 400 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.^[16]^[31] It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone.^[16] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.^[32] Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.^[33]

Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.^[34]^[35]

Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers.^[5] The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC₅₀ values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC₅₀ values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.^[4]

Resistance

Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family.^[36]^[37]

Pharmacokinetics

When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola.^[38] Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.

History

Ketoconazole was discovered in 1976 at Janssen Pharmaceutica.^[39] It was initially introduced in 1977, followed by introduction in the United States in 1981.^[3] It was introduced as the prototypical drug of the imidazole antifungals.^[40] Oral ketoconazole has been replaced with oral itraconazole for many mycoses.^[40]

Society and culture

Name

Ketoconazole is the drug's INN, USAN, BAN, and JAN.^[41]^[42]

References

^ "Ketoconazole". Merriam-Webster Dictionary.
^ "Ketoconazole". Dictionary.com Unabridged. Random House.
^ ^a ^b Larry E. Millikan (19 April 2016). Drug Therapy in Dermatology. CRC Press. pp. 82–. ISBN 978-0-203-90831-0.
^ ^a ^b ^c "Assessment report: Ketoconazole HRA" (PDF). www.ema.europa.eu. European Medicines Agency. Committee for Medicinal Products for Human Use. Retrieved 26 August 2016.
^ ^a ^b Arakaki R, Welles B (February 2010). "Ketoconazole enantiomer for the treatment of diabetes mellitus". Expert Opinion on Investigational Drugs. 19 (2): 185–94. PMID 20047506. doi:10.1517/13543780903381411.
^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
^ "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26.
^ TGA. 10 October 2013 Oral ketoconazole (Nizoral) 200 mg tablets: Product deregistration
^ http://www.tga.gov.au/safety/alerts-medicine-oral-ketoconazole-131010.htm
^ "国家食品药品监督管理总局关于停止生产销售使用酮康唑口服制剂的公告（2015年第85号）" (in Chinese). China Food and Drug Administration. 2015-06-25. Retrieved 2015-07-02.
^ ^a ^b ^c Phillips RM, Rosen T (2013). "Topical Antifungal Agents". In Wolverton SE. Comprehensive Dermatologic Therapy (3rd ed.). Philadelphia: Saunders. pp. 460–472. ISBN 978-1-4377-2003-7.
^ Neider R, Fritsch PO (2012). "Other Eczematous Eruptions". In Bolognia JL. Dermatology (3rd ed.). Philadelphia: Saunders. pp. 219–221. ISBN 9780723435716.
^ Young BK, Brodell RT, Cooper KD (2013). "Therapeutic Shampoos". In Wolverton SE. Comprehensive Dermatologic Therapy (3rd ed.). Philadelphia: Saunders. pp. 562–569. ISBN 978-1-4377-2003-7.
^ ^a ^b ^c ^d Finkel R, Cubeddu LX, Clark MA (2009). Pharmacology (4th ed.). Baltimore: Lippincott Williams & Wilkins. p. 411.
^ Kauffman CA (2004). "Introduction to the Mycoses". In Goldman L; Ausiello, D. Cecil Textbook of Medicine (22nd ed.). Philadelphia: Saunders. p. 2043. ISBN 0-7216-9652-X.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1197–. ISBN 978-0-7817-1750-2.
^ "MedScape". Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management. Nature Publishing Group. Retrieved 18 April 2015.
^ ^a ^b Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (May 1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes". The Journal of Clinical Investigation. 71 (5): 1495–9. PMC 437014 . PMID 6304148. doi:10.1172/JCI110903.
^ Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P (2008). DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology (8th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 1443. ISBN 9780781772075.
^ Loli P, Berselli ME, Tagliaferri M (December 1986). "Use of ketoconazole in the treatment of Cushing's syndrome". The Journal of Clinical Endocrinology and Metabolism. 63 (6): 1365–71. PMID 3023421. doi:10.1210/jcem-63-6-1365.
^ McElwee KJ, Shapiro JS (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Letter. 17 (6): 1–4. PMID 22735503.
^ Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE (1998). "Ketoconazole shampoo: effect of long-term use in androgenic alopecia". Dermatology. 196 (4): 474–7. PMID 9669136. doi:10.1159/000017954.
^ Piérard-Franchimont C, Goffin V, Henry F, Uhoda I, Braham C, Piérard GE (October 2002). "Nudging hair shedding by antidandruff shampoos. A comparison of 1% ketoconazole, 1% piroctone olamine and 1% zinc pyrithione formulations". International Journal of Cosmetic Science. 24 (5): 249–56. PMID 18498517. doi:10.1046/j.1467-2494.2002.00145.x.
^ Khandpur S, Suman M, Reddy BS (August 2002). "Comparative efficacy of various treatment regimens for androgenetic alopecia in men". The Journal of Dermatology. 29 (8): 489–98. PMID 12227482. doi:10.1111/j.1346-8138.2002.tb00314.x.
^ Evans, K. C.; Peterson, A. C.; Ruiz, H. E.; Costabile, R. A. (2004-08-01). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research. 16 (4): 346–349. ISSN 0955-9930. PMID 14973533. doi:10.1038/sj.ijir.3901160.
^ KuKanich B (January 2008). "A review of selected systemic antifungal drugs for use in dogs and cats". Veterinary Medicine.
^ Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy". Postgraduate Medical Journal. 66 (773): 221–3. PMC 2429473 . PMID 2362890. doi:10.1136/pgmj.66.773.221.
^ Berwaerts J, Verhelst J, Mahler C, Abs R (June 1999). "Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature". Gynecological Endocrinology. 13 (3): 175–82. PMID 10451809. doi:10.3109/09513599909167552.
^ Kazy Z, Puhó E, Czeizel AE (March 2005). "Population-based case-control study of oral ketoconazole treatment for birth outcomes". Congenital Anomalies. 45 (1): 5–8. PMID 15737124. doi:10.1111/j.1741-4520.2005.00053.x.
^ ^a ^b "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems". FDA Drug Safety Communication. U.S. Food and Drug Administration. July 26, 2013. Retrieved November 23, 2013.
^ Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD (May 1989). "Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group". Urology. 33 (5): 411–5. PMID 2652864. doi:10.1016/0090-4295(89)90037-X.
^ De Coster R, Wouters W, Bruynseels J (January 1996). "P450-dependent enzymes as targets for prostate cancer therapy". The Journal of Steroid Biochemistry and Molecular Biology. 56 (1-6 Spec No): 133–43. PMID 8603034. doi:10.1016/0960-0760(95)00230-8.
^ Eil C (August 1992). "Ketoconazole binds to the human androgen receptor". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 24 (8): 367–70. PMID 1526623. doi:10.1055/s-2007-1003337.
^ Loose DS, Stover EP, Feldman D (July 1983). "Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells". The Journal of Clinical Investigation. 72 (1): 404–8. PMC 1129197 . PMID 6135709. doi:10.1172/jci110982.
^ Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (July 2006). "Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor". Molecular Pharmacology. 70 (1): 329–39. PMID 16608920. doi:10.1124/mol.105.022046.
^ Cartledge JD, Midgley J, Gazzard BG (December 1997). "Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis". Aids. 11 (15): 1839–44. PMID 9412702. doi:10.1097/00002030-199715000-00008.
^ Sanglard D, Ischer F, Monod M, Bille J (February 1997). "Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene". Microbiology. 143 ( Pt 2) (Pt 2): 405–16. PMID 9043118. doi:10.1099/00221287-143-2-405.
^ Chin TW, Loeb M, Fong IW (August 1995). "Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole". Antimicrobial Agents and Chemotherapy. 39 (8): 1671–5. PMC 162805 . PMID 7486898. doi:10.1128/AAC.39.8.1671.
^ Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (August 1979). "Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent". Journal of Medicinal Chemistry. 22 (8): 1003–5. PMID 490531. doi:10.1021/jm00194a023.
^ ^a ^b David E. Golan (2008). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 624–. ISBN 978-0-7817-8355-2.
^ J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 720–. ISBN 978-1-4757-2085-3.
^ I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 159–. ISBN 978-94-011-4439-1.

External links

PubPK | Ketoconazole pharmacokinetics^{[dead link]}
Eil C (August 1992). "Ketoconazole binds to the human androgen receptor". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 24 (8): 367–70. PMID 1526623. doi:10.1055/s-2007-1003337.
Janssen Pharmaceutica | Nizoral

UpToDate Contents

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1. 癜風 tinea versicolor
2. 去勢抵抗性前立腺癌に対する二次内分泌療法 secondary endocrine therapies for castration resistant prostate cancer
3. 副腎皮質機能亢進症の内科的治療（クッシング症候群） medical therapy of hypercortisolism cushings syndrome
4. ヘイリー・ヘイリー病（良性家族性天疱瘡） hailey hailey disease benign familial pemphigus
5. 播種性前立腺癌に対する治療の概要 overview of the treatment of disseminated prostate cancer

English Journal

Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline.

Utoh M, Murayama N, Uno Y, Onose Y, Hosaka S, Fujino H, Shimizu M, Iwasaki K, Yamazaki H.SourceShin Nippon Biomedical Laboratories, Ltd., Pharmacokinetics and Bioanalysis Center , Kainan , Japan .
Xenobiotica; the fate of foreign compounds in biological systems.Xenobiotica.2013 Dec;43(12):1037-42. doi: 10.3109/00498254.2013.793874. Epub 2013 May 16.
Abstract 1. Caffeine (1,3,7-trimethylxanthine) is a phenotyping substrate for human cytochrome P450 1A2. 3-N-Demethylation of caffeine is the main human metabolic pathway, whereas monkeys extensively mediate the 7-N-demethylation of caffeine to form pharmacological active theophylline. 2. Roles of m
PMID 23679834

Transungual delivery of ketoconazole using novel lacquer formulation.

Hafeez F, Hui X, Chiang A, Hornby S, Maibach H.SourceDermatology Department, University of California, San Francisco, 90 Medical Center Way, Surge Building, Room 110, San Francisco, CA 94143-0989, USA. Electronic address: farhaanhafeez@gmail.com.
International journal of pharmaceutics.Int J Pharm.2013 Nov 18;456(2):357-61. doi: 10.1016/j.ijpharm.2013.08.082. Epub 2013 Sep 9.
Onychomycosis, a common fungal infection of the nail, can have a substantial impact on quality of life. The success of topical therapy for onychomycosis depends on effective penetration, which can be enhanced using an appropriate delivery method. This study evaluated the effectiveness of a novel top
PMID 24029171

Experiments for a systematic comparison between stable-isotope-(deuterium) labeling and radio-((14)C) labeling for the elucidation of the in vitro metabolic pattern of pharmaceutical drugs.

Grunwald H, Hargreaves P, Gebhardt K, Klauer D, Serafyn A, Schmitt-Hoffmann A, Schleimer M, Schlotterbeck G, Wind M.SourceBasilea Pharmaceutica International AG, Basel, Switzerland.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2013 Nov;85:138-44. doi: 10.1016/j.jpba.2013.07.004. Epub 2013 Jul 19.
A systematic comparison between two labeling approaches for the investigation of the in vitro metabolic pattern of pharmaceutical drugs was performed by examining the use of (i) radiolabeled drugs analyzed with LC-MS-offline radiodetection and (ii) stable-isotope labeled drugs, used in a defined mix
PMID 23933567

Japanese Journal

In Vitro Susceptibility of Malassezia pachydermatis Isolates from Canine Skin with Atopic Dermatitis to Ketoconazole and Itraconazole in East Asia

WATANABE Shion,KOIKE Anna,KANO Rui,NAGATA Masahiko,CHEN Charles,HWANG Cheol-Yong,HASEGAWA Atsuhiko,KAMATA Hiroshi
Journal of Veterinary Medical Science, 2013
… pachydermatis isolates to ketoconazole (KTZ) and itraconazole (ITZ) obtained from AD lesions of canines in Japan, Korea and Taiwan. …
NAID 130003382408

Metabolism of (+)-Terpinen-4-ol by Cytochrome P450 Enzymes in Human Liver Microsomes

Haigou Risa,Miyazawa Mitsuo
Journal of Oleo Science 61(1), 35-43, 2012
… Second, oxidation of (+)-terpinen-4-ol was inhibited by (+)-menthofuran and ketoconazole, inhibitors known to be specific for these enzymes. …
NAID 130001882204

In Vitro Activities of Antifungal Agents against Clinical Isolates of Dermatophytes from Animals

ITOI Sayuri,KANO Rui,HASEGAWA Atsuhiko [他],KAMATA Hiroshi
Journal of Veterinary Medical Science 74(8), 1067-1069, 2012
… The in vitro susceptibility of 54 clinical isolates from animal dermatophytoses to ketoconazole (KTZ), itaconazole (ITZ) and terbinafine (TFN) was measured using microdilution assay (CLSI M38-A2 test) and by the E-test (KTZ and ITZ). …
NAID 130001879810

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★リンクテーブル★

リンク元	「薬理学」「ケトコナゾール」

「薬理学」

Ketoconazole
	(2R,4S)-(+)-ketoconazole (top); (2S,4R)-(−)-ketoconazole (bottom)
Clinical data
Pronunciation	/ˌkiːtoʊˈkoʊnəˌzoʊl, -zɒl/
Trade names	Nizoral
AHFS/Drugs.com	Monograph
MedlinePlus	a682816
License data	US FDA: Ketoconazole;
Pregnancy; category	AU: B3; US: C (Risk not ruled out); ;
Routes of; administration	Oral (tablets), topical (cream, shampoo, solution)
ATC code	J02AB02 (WHO) D01AC08 (WHO) G01AF11 (WHO);
Legal status
Legal status	UK: POM (Prescription only); US: OTC;
Pharmacokinetic data
Bioavailability	Oral: 37–97%
Protein binding	84 to 99%
Metabolism	Extensive liver (predominantly oxidation, O-dealkylation)
Metabolites	N-deacetyl ketoconazole
Biological half-life	Biphasic
Excretion	Biliary (major) and renal
Identifiers
	IUPAC name 1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone;
CAS Number	65277-42-1 ;
PubChem CID	3823;
IUPHAR/BPS	2568;
DrugBank	DB01026 ;
ChemSpider	401695 ;
UNII	R9400W927I;
KEGG	D00351 ;
ChEBI	CHEBI:48336 ;
ChEMBL	CHEMBL75 ;
PDB ligand	KTN (PDBe, RCSB PDB);
ECHA InfoCard	100.059.680
Chemical and physical data
Formula	C26H28Cl2N4O4
Molar mass	531.431 g/mol
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES O=C(N5CCN(c4ccc(OC[C@@H]1O[C@](OC1)(c2ccc(Cl)cc2Cl)Cn3ccnc3)cc4)CC5)C ;
	InChI InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1 ; Key:XMAYWYJOQHXEEK-OZXSUGGESA-N ;
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英: pharmacology
関: drug entries

定義

生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

薬の生物系に対する相互作用：薬理作用 <-化学の視点
生物系の薬に対する相互作用：薬物動態 <-生物の視点

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β₂ agonist	albuterol
～tidine	H₂ antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a₁ antagonist	prazosin

薬一覧

薬物代謝

薬理動態

神経伝達物質

貧血治療薬

甲状腺関連物質

甲状腺ホルモン製剤

レボチロキシン levothyroxine
リオチニシン liothyronine

抗甲状腺薬

痛風治療薬

痛風発作予防薬

コルヒチン colchicine

尿酸排泄促進薬

尿酸生成抑制薬

アロプリノール allopurinol

「ケトコナゾール」

　　[★]

英: ketoconazole
商: ケトコナゾール、ケトパミン、ニゾラール、ニトラゼン、プルナ
関: 抗真菌薬; 寄生性皮ふ疾患用剤

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[2] "Ketoconazole". Dictionary.com Unabridged. Random House.

[Millikan2016-3] Larry E. Millikan (19 April 2016). Drug Therapy in Dermatology. CRC Press. pp. 82–. ISBN 978-0-203-90831-0.

[AR-4] "Assessment report: Ketoconazole HRA" (PDF). www.ema.europa.eu. European Medicines Agency. Committee for Medicinal Products for Human Use. Retrieved 26 August 2016.

[Arakak-5] Arakaki R, Welles B (February 2010). "Ketoconazole enantiomer for the treatment of diabetes mellitus". Expert Opinion on Investigational Drugs. 19 (2): 185–94. PMID 20047506. doi:10.1517/13543780903381411.

[AMH-6] Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.

[url_ema-7] "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26.

[8] TGA. 10 October 2013 Oral ketoconazole (Nizoral) 200 mg tablets: Product deregistration

[9] ttp://www.tga.gov.au/safety/alerts-medicine-oral-ketoconazole-131010.htm

[10] "国家食品药品监督管理总局关于停止生产销售使用酮康唑口服制剂的公告（2015年第85号）" (in Chinese). China Food and Drug Administration. 2015-06-25. Retrieved 2015-07-02.

[phillips-11] Phillips RM, Rosen T (2013). "Topical Antifungal Agents". In Wolverton SE. Comprehensive Dermatologic Therapy (3rd ed.). Philadelphia: Saunders. pp. 460–472. ISBN 978-1-4377-2003-7.

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[Medscape-keto-17] "MedScape". Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management. Nature Publishing Group. Retrieved 18 April 2015.

[pmid6304148-18] Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (May 1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes". The Journal of Clinical Investigation. 71 (5): 1495–9. PMC 437014 . PMID 6304148. doi:10.1172/JCI110903.

[zelefsky-19] Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P (2008). DeVita VT, Lawrence TS, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology (8th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 1443. ISBN 9780781772075.

[Cushing-20] Loli P, Berselli ME, Tagliaferri M (December 1986). "Use of ketoconazole in the treatment of Cushing's syndrome". The Journal of Clinical Endocrinology and Metabolism. 63 (6): 1365–71. PMID 3023421. doi:10.1210/jcem-63-6-1365.

[pmid22735503-21] McElwee KJ, Shapiro JS (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Letter. 17 (6): 1–4. PMID 22735503.

[pmid9669136-22] Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE (1998). "Ketoconazole shampoo: effect of long-term use in androgenic alopecia". Dermatology. 196 (4): 474–7. PMID 9669136. doi:10.1159/000017954.

[pmid18498517-23] Piérard-Franchimont C, Goffin V, Henry F, Uhoda I, Braham C, Piérard GE (October 2002). "Nudging hair shedding by antidandruff shampoos. A comparison of 1% ketoconazole, 1% piroctone olamine and 1% zinc pyrithione formulations". International Journal of Cosmetic Science. 24 (5): 249–56. PMID 18498517. doi:10.1046/j.1467-2494.2002.00145.x.

[pmid12227482-24] Khandpur S, Suman M, Reddy BS (August 2002). "Comparative efficacy of various treatment regimens for androgenetic alopecia in men". The Journal of Dermatology. 29 (8): 489–98. PMID 12227482. doi:10.1111/j.1346-8138.2002.tb00314.x.

[25] Evans, K. C.; Peterson, A. C.; Ruiz, H. E.; Costabile, R. A. (2004-08-01). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research. 16 (4): 346–349. ISSN 0955-9930. PMID 14973533. doi:10.1038/sj.ijir.3901160.

[KuKanich_2008-26] KuKanich B (January 2008). "A review of selected systemic antifungal drugs for use in dogs and cats". Veterinary Medicine.

[pregnancy_1-27] Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy". Postgraduate Medical Journal. 66 (773): 221–3. PMC 2429473 . PMID 2362890. doi:10.1136/pgmj.66.773.221.

[pregnancy_2-28] Berwaerts J, Verhelst J, Mahler C, Abs R (June 1999). "Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature". Gynecological Endocrinology. 13 (3): 175–82. PMID 10451809. doi:10.3109/09513599909167552.

[Giant_Hungarian_Human_Birth_Defects_Study-29] Kazy Z, Puhó E, Czeizel AE (March 2005). "Population-based case-control study of oral ketoconazole treatment for birth outcomes". Congenital Anomalies. 45 (1): 5–8. PMID 15737124. doi:10.1111/j.1741-4520.2005.00053.x.

[fda_warning-30] "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems". FDA Drug Safety Communication. U.S. Food and Drug Administration. July 26, 2013. Retrieved November 23, 2013.

[pmid2652864-31] Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD (May 1989). "Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group". Urology. 33 (5): 411–5. PMID 2652864. doi:10.1016/0090-4295(89)90037-X.

[pmid8603034-32] De Coster R, Wouters W, Bruynseels J (January 1996). "P450-dependent enzymes as targets for prostate cancer therapy". The Journal of Steroid Biochemistry and Molecular Biology. 56 (1-6 Spec No): 133–43. PMID 8603034. doi:10.1016/0960-0760(95)00230-8.

[pmid1526623-33] Eil C (August 1992). "Ketoconazole binds to the human androgen receptor". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 24 (8): 367–70. PMID 1526623. doi:10.1055/s-2007-1003337.

[pmid6135709-34] Loose DS, Stover EP, Feldman D (July 1983). "Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells". The Journal of Clinical Investigation. 72 (1): 404–8. PMC 1129197 . PMID 6135709. doi:10.1172/jci110982.

[pmid16608920-35] Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (July 2006). "Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor". Molecular Pharmacology. 70 (1): 329–39. PMID 16608920. doi:10.1124/mol.105.022046.

[36] Cartledge JD, Midgley J, Gazzard BG (December 1997). "Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis". Aids. 11 (15): 1839–44. PMID 9412702. doi:10.1097/00002030-199715000-00008.

[37] Sanglard D, Ischer F, Monod M, Bille J (February 1997). "Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene". Microbiology. 143 ( Pt 2) (Pt 2): 405–16. PMID 9043118. doi:10.1099/00221287-143-2-405.

[38] Chin TW, Loeb M, Fong IW (August 1995). "Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole". Antimicrobial Agents and Chemotherapy. 39 (8): 1671–5. PMC 162805 . PMID 7486898. doi:10.1128/AAC.39.8.1671.

[Heeres_1979-39] Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (August 1979). "Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent". Journal of Medicinal Chemistry. 22 (8): 1003–5. PMID 490531. doi:10.1021/jm00194a023.

[Golan2008-40] David E. Golan (2008). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 624–. ISBN 978-0-7817-8355-2.

[Elks2014-41] J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 720–. ISBN 978-1-4757-2085-3.

[MortonHall2012-42] I.K. Morton; Judith M. Hall (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 159–. ISBN 978-94-011-4439-1.

v t e Other dermatological preparations (D11)
Anti-seborrheics	Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Antifungals Bifonazole Cetrimonium bromide (cetrimide) Ciclopirox olamine (ciclopirox) Climbazole Clotrimazole Ketoconazole Miconazole Piroctone olamine Selenium disulfide (selenium sulfide) Xenysalate Zinc pyrithione (pyrithione zinc) Antihistamines Calcineurin inhibitors Cyclosporin Pimecrolimus Tacrolimus Isotretinoin Keratolytics Coal tar Resorcinol Salicylic acid Sulfur Urea (urea-containing cream) Lithium salts Lithium gluconate Lithium succinate Topical corticosteroids (e.g., hydrocortisone)
Skin lightening	Hydroquinone Mequinol Monobenzone
Skin darkening	Afamelanotide Melanotan II
Anti-inflammatories	Oxaceprol Gamolenic acid Pimecrolimus Tacrolimus Alitretinoin
Alopecia treatments	5α-Reductase inhibitors Alfatradiol Finasteride Dutasteride Saw palmetto extract Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Topilutamide (fluridil) Potassium channel openers Minoxidil Others Nepidermin
Hair growth inhibitors	5α-Reductase inhibitors Dutasteride Finasteride Antiandrogens Bicalutamide Cyproterone acetate Flutamide Spironolactone Eflornithine
Others	Androgens (e.g., testosterone) Brimonidine Calcium gluconate Estrogens (e.g., estradiol) Hyaluronic acid Magnesium sulfate Pregnenolone acetate Progestogens (e.g., progesterone) Povidone-iodine Tiratricol

v t e Piperazines
Simple piperazines (no additional rings)	1-Cyclohexylpiperazine Aminoethylpiperazine Diethylcarbamazine HEPPS Midafotel Piperazine PIPES
Phenylpiperazines	Acaprazine Antrafenine Aripiprazole Batoprazine Bifeprunox BRL-15,572 Ciprofloxacin CSP-2503 Dapiprazole DCPP DMPP Diphenylpiperazine Dropropizine EGIS-12,233 Elopiprazole Eltoprazine Enpiprazole Ensaculin Etoperidone Flesinoxan Flibanserin Fluprazine Itraconazole Ketoconazole Levodropropizine Lorpiprazole mCPP Mefway MeOPP Mepiprazole Naftopidil Naluzotan Naphthylpiperazine Nefazodone Niaprazine Oxypertine Pardoprunox pCPP pFPP Posaconazole S-14,506 S-14,671 S-15,535 SB-258,585 SB-271,046 SB-357,134 SB-399,885 Sonepiprazole TFMPP Tolpiprazole Trazodone Urapidil Vesnarinone Vilazodone Vortioxetine WAY-100,135 WAY-100,635
Benzylpiperazines	2C-B-BZP Befuraline Bifeprunox Buclizine BZP Chlorbenzoxamine DBZP Fipexide Imatinib MBZP MDBZP Meclozine Methoxypiperamide Piberaline Piribedil Sunifiram Trimetazidine Vesnarinone
Diphenylalkylpiperazines (benzhydrylalkylpiperazines)	Almitrine Amperozide BRL-15,572 Buclizine BW373U86 Cetirizine Chlorbenzoxamine Chlorcyclizine Cinnarizine Clocinizine Cyclizine DBL-583 Diphenylmethylpiperazine Dotarizine DPI-221 DPI-287 DPI-3290 GBR-12,783 GBR-12,935 GBR-13,069 GBR-13,098 GBR-13,119 Hydroxyzine Lidoflazine Manidipine Meclozine Oxatomide SNC-80 Vanoxerine
Pyrimidinylpiperazines	Buspirone Dasatinib Eptapirone Gepirone Ipsapirone Piribedil Prazitone Pyrimidinylpiperazine Revospirone Tandospirone Tirilazad Trimazosin Umespirone Zalospirone
Pyridinylpiperazines	Atevirdine Azaperone Delavirdine Mirtazapine Pyridinylpiperazine
Benzo(iso)thiazolylpiperazines	Lurasidone Perospirone Revospirone Tiospirone Ziprasidone
Tricyclics (piperazine attached via side chain)	Amoxapine Clopenthixol Clorotepine Clozapine Cyanothepin Doclothepin Docloxythepin Flupentixol Fluphenazine Isofloxythepin Loxapine Meperathiepin Metitepine Octomethothepin Olanzapine Opipramol Oxyclothepin Oxyprothepin Peradithiepin Perathiepin Perazine Perphenazine Pirenzepine Prochlorperazine Thiethylperazine Thiothixene Trifluoperazine Trifluthepin Zuclopenthixol
Others/Uncategorized	6-Nitroquipazine Azimilide Cinepazet Cinepazic acid Cinepazide Cyclohexylpiperazine EGIS-7625 Hexocyclium Indinavir JNJ-7777120 Lodenafil Mirodenafil PB-28 Quipazine Ranolazine SA-4503 Sildenafil Tadalafil Vardenafil VUF-6002 Zipeprol

Clinical data
(2R,4S)-(+)-ketoconazole (top) (2S,4R)-(−)-ketoconazole (bottom)
Pronunciation	/ˌkiːtoʊˈkoʊnəˌzoʊl, -zɒl/^[1]^[2]
Trade names	Nizoral
AHFS/Drugs.com	Monograph
MedlinePlus	a682816
License data	US FDA: Ketoconazole
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral (tablets), topical (cream, shampoo, solution)
ATC code	J02AB02 (WHO) D01AC08 (WHO) G01AF11 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: OTC
Pharmacokinetic data
Bioavailability	Oral: 37–97%^[3]
Protein binding	84 to 99%
Metabolism	Extensive liver (predominantly oxidation, O-dealkylation)
Metabolites	N-deacetyl ketoconazole
Biological half-life	Biphasic
Excretion	Biliary (major) and renal^[4]
Identifiers
IUPAC name 1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
CAS Number	65277-42-1^Y
PubChem CID	3823
IUPHAR/BPS	2568
DrugBank	DB01026^Y
ChemSpider	401695^Y
UNII	R9400W927I
KEGG	D00351^Y
ChEBI	CHEBI:48336^Y
ChEMBL	CHEMBL75^Y
PDB ligand	KTN (PDBe, RCSB PDB)
ECHA InfoCard	100.059.680
Chemical and physical data
Formula	C₂₆H₂₈Cl₂N₄O₄
Molar mass	531.431 g/mol
3D model (JSmol)	Interactive image
Chirality	Racemic mixture^[4]^[5]
SMILES O=C(N5CCN(c4ccc(OC[C@@H]1O[C@](OC1)(c2ccc(Cl)cc2Cl)Cn3ccnc3)cc4)CC5)C
InChI InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1^Y Key:XMAYWYJOQHXEEK-OZXSUGGESA-N^Y
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案内

ketoconazole