Ketoconazole

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Ketoconazole
Ketoconazole enantiomers.svg
(2R,4S)-(+)-ketoconazole (top)
(2S,4R)-(−)-ketoconazole (bottom)
Systematic (IUPAC) name
1-[4-(4-{[(2R,4S)-rel-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one
Clinical data
Pronunciation /ˌkiːtoʊˈkoʊnəˌzoʊl, -zɒl/[1][2]
Trade names Nizoral
AHFS/Drugs.com Monograph
MedlinePlus a682816
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral (tablets), topical (cream, shampoo, solution)
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: OTC
Pharmacokinetic data
Bioavailability Highly variable; ~81.2% (oral, humans)
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[3]
Identifiers
CAS Number 65277-42-1 YesY
ATC code J02AB02 (WHO) D01AC08 (WHO) G01AF11 (WHO)
PubChem CID 456201
IUPHAR/BPS 2568
DrugBank DB01026 YesY
ChemSpider 401695 YesY
UNII R9400W927I YesY
KEGG D00351 YesY
ChEBI CHEBI:48336 YesY
ChEMBL CHEMBL75 YesY
PDB ligand ID KTN (PDBe, RCSB PDB)
Chemical data
Formula C26H28Cl2N4O4
Molar mass 531.431 g/mol
Chirality Racemic mixture[3][4]
3D model (Jmol) Interactive image
  (verify)

Ketoconazole (INN, USAN, BAN, JAN) 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).[5]

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.[6] The oral formulation of ketoconazole was discontinued in Australia in 2013[7][8] and in China in 2015.[9]

Medical uses[edit]

Antifungal[edit]

Topical antifungal[edit]

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.[10] 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.[10][11][12]

Systemic antifungal[edit]

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).[13] First synthesized in 1977,[10] ketoconazole was the first orally-active azole antifungal medication.[13] 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.[13][14]

Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.[15]

Antiandrogenic and antiglucocorticoid[edit]

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.[13][15] Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase,[15] which convert pregnenolone into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol.[16] All of these enzymes are mitochondrial cytochrome p450 enzymes.[17] 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[15][18] and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome.[19] However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency.[15] Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty.[15] 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.[15]

Veterinary[edit]

This medication is also sometimes prescribed by veterinarians for use on pets, often as unflavoured tablets that may need to be cut to smaller size for correct dosage.[20]

Mechanism of action[edit]

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).[21] 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.[15][22] 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.[15] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[23] 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.[24]

Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.[25][26]

Administration and absorption[edit]

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.[27] Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.

Resistance[edit]

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.[28][29]

Off-label uses[edit]

Hair loss[edit]

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.[30]

Limited clinical studies suggest ketoconazole shampoo used either alone[31][32] or in combination with other treatments[33] may be useful in reducing hair loss.

Adverse effects[edit]

It 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,[34][35] 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.[36]

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.[37]

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.[37]

Chemistry[edit]

Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers.[4] 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.[3]

History[edit]

Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals.[38]

See also[edit]

References[edit]

  1. ^ "Ketoconazole". Merriam-Webster Dictionary. 
  2. ^ "Ketoconazole". Dictionary.com Unabridged. Random House. 
  3. ^ 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. 
  4. ^ 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. doi:10.1517/13543780903381411. PMID 20047506. 
  5. ^ Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  6. ^ "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26. 
  7. ^ TGA. 10 October 2013 Oral ketoconazole (Nizoral) 200 mg tablets: Product deregistration
  8. ^ http://www.tga.gov.au/safety/alerts-medicine-oral-ketoconazole-131010.htm
  9. ^ "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. 
  10. ^ 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. 
  11. ^ Neider R, Fritsch PO (2012). "Other Eczematous Eruptions". In Bolognia JL. Dermatology (3rd ed.). Philadelphia: Saunders. pp. 219–221. ISBN 9780723435716. 
  12. ^ 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. 
  13. ^ a b c d Finkel R, Cubeddu LX, Clark MA (2009). Pharmacology (4th ed.). Baltimore: Lippincott Williams & Wilkins. p. 411. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ "MedScape". Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management. Nature Publishing Group. Retrieved 18 April 2015. 
  17. ^ 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. doi:10.1172/JCI110903. PMC 437014Freely accessible. PMID 6304148. 
  18. ^ 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. 
  19. ^ 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. doi:10.1210/jcem-63-6-1365. PMID 3023421. 
  20. ^ KuKanich B (January 2008). "A review of selected systemic antifungal drugs for use in dogs and cats". Veterinary Medicine. 
  21. ^ 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. doi:10.1172/JCI110903. PMC 437014Freely accessible. PMID 6304148. 
  22. ^ 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. doi:10.1016/0090-4295(89)90037-X. PMID 2652864. 
  23. ^ 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. doi:10.1016/0960-0760(95)00230-8. PMID 8603034. 
  24. ^ 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. doi:10.1055/s-2007-1003337. PMID 1526623. 
  25. ^ 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. doi:10.1172/jci110982. PMC 1129197Freely accessible. PMID 6135709. 
  26. ^ 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. doi:10.1124/mol.105.022046. PMID 16608920. 
  27. ^ 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. doi:10.1128/AAC.39.8.1671. PMC 162805Freely accessible. PMID 7486898. 
  28. ^ 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. doi:10.1097/00002030-199715000-00008. PMID 9412702. 
  29. ^ 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. doi:10.1099/00221287-143-2-405. PMID 9043118. 
  30. ^ McElwee KJ, Shapiro JS (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Letter. 17 (6): 1–4. PMID 22735503. 
  31. ^ 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. doi:10.1159/000017954. PMID 9669136. 
  32. ^ 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. doi:10.1046/j.1467-2494.2002.00145.x. PMID 18498517. 
  33. ^ 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. doi:10.1111/j.1346-8138.2002.tb00314.x. PMID 12227482. 
  34. ^ 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. doi:10.1136/pgmj.66.773.221. PMC 2429473Freely accessible. PMID 2362890. 
  35. ^ 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. doi:10.3109/09513599909167552. PMID 10451809. 
  36. ^ 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. doi:10.1111/j.1741-4520.2005.00053.x. PMID 15737124. 
  37. ^ 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. 
  38. ^ 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. doi:10.1021/jm00194a023. PMID 490531. 

Further reading[edit]

  • Piérard-Franchimont C, Goffin V, Decroix J, Piérard GE (2002). "A multicenter randomized trial of ketoconazole 2% and zinc pyrithione 1% shampoos in severe dandruff and seborrheic dermatitis". Skin Pharmacology and Applied Skin Physiology. 15 (6): 434–41. doi:10.1159/000066452. PMID 12476017. 

External links[edit]

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