Ketoconazole

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Ketoconazole
Ketoconazole2DACS.svg
Ketoconazole3Dan.gif
Systematic (IUPAC) name
1-[4-(4-{[(2R,4S)-2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]ethan-1-one
Clinical data
Trade names Nizoral
AHFS/Drugs.com monograph
MedlinePlus a682816
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral, topical
Pharmacokinetic data
Bioavailability Variable
Protein binding 84 to 99%
Metabolism Hepatic
Half-life Biphasic:
Excretion Biliary and renal
Identifiers
CAS number 65277-42-1 YesY
ATC code J02AB02 D01AC08 G01AF11
PubChem CID 456201
IUPHAR ligand 2568
DrugBank DB01026
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 
Mol. mass 531.431 g/mol
 YesY (what is this?)  (verify)

Ketoconazole /ˌktɵˈknəzɒl/ is a synthetic, imidazole antifungal medication 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).[1]

The less toxic and generally more effective triazole antifungal agents fluconazole and itraconazole are usually preferred for systemic use. The European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) has 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.[2] In Australia, the oral formulation of ketoconazole has already been discontinued.[1][3]

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.[4] 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.[4][5][6]

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).[7] First synthesized in 1977,[4] ketoconazole was the first orally active azole antifungal medication.[7] 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.[7][8]

Antiandrogenic and antiglucocorticoid[edit]

The side effects of ketoconazole are sometimes harnessed in the treatment of nonfungal conditions. While ketoconazole blocks the synthesis of the plant sterol ergosterol in fungi, in human beings it inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol.[7] Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used as a second-line treatment for certain forms of advanced prostate cancer[9] and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome.[10]

Veterinary[edit]

This medication 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.[11]

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 14-alpha-demethylase (P45014DM).[12] 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.[13] It produces this effect through inhibition of cytochrome P450 isozyme 3A4 and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used as a treatment for androgen-dependent prostate cancer.[14] Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for androgen receptor binding. This effect is thought to be quite weak, even with high oral doses of ketoconazole.[15]

Administration & 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.[16] 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.

Off label uses[edit]

Hair loss[edit]

Nizoral (ketoconazole) 2% shampoo

Ketoconazole shampoo in conjunction with systemic antiandrogens treatment has been used off label to treat androgenic alopecia. Its anti-fungal properties reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[17] Furthermore ketoconazole blocks the local synthesis of dihydrotestosterone in the scalp as well as acts as an antagonist of the androgen receptor. Hence it has been hypothesized that ketoconazole when used together with systemic antiandrogens may result in a more complete blockade of androgen receptor in the scalp and consequently may lead to a more effective treatment of androgenic alopecia.[18]

Limited clinical studies suggest that ketoconazole shampoo used either alone[19][20] or in combination with other treatments[21] 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,[22][23] 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.[24]

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.[25]

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.[25]

Synthesis[edit]

The first racemic synthesis of ketoconazole was published in 1979. In this synthesis, cis- and trans-isomers were separated by crystallization because only the two cis-enantiomers are used in the commercially available drug.[26]

Synthesis of ketoconazole (8)

The synthesis was started with dichloroacetophenone (1) and glycerine. The ketal was directly brominated to yield alcohol 2. This was further transformed into the corresponding benzoate ester 3 and at this stage cis- and trans-isomers were separated. The imidazole residue was then introduced followed by a basic hydrolysis of the ester moiety. The free hydroxyl group of 5 was converted into the mesylate and was then replaced by substituent 7 to yield ketoconazole 8 in six steps and an overall yield of 12%.

History[edit]

Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals.[26]

References[edit]

  1. ^ a b Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  2. ^ "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26. 
  3. ^ http://www.tga.gov.au/safety/alerts-medicine-oral-ketoconazole-131010.htm
  4. ^ 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. 
  5. ^ Neider R, Fritsch PO (2012). "Other Eczematous Eruptions". In Bolognia JL. Dermatology (3rd ed.). Philadelphia: Saunders. pp. 219–221. ISBN 9780723435716. 
  6. ^ 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. 
  7. ^ a b c d Finkel R, Cubeddu LX, Clark MA (2009). Pharmacology (4th ed.). Baltimore: Lippincott Williams & Wilkins. p. 411. 
  8. ^ 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. 
  9. ^ Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P (2008). DeVita VT, Lawrence TS, Rosenberg SA, ed. Cancer: Principles & Practice of Oncology (8th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 1443. ISBN 9780781772075. 
  10. ^ Loli P, Berselli ME, Tagliaferri M (December 1986). "Use of ketoconazole in the treatment of Cushing's syndrome". J. Clin. Endocrinol. Metab. 63 (6): 1365–71. doi:10.1210/jcem-63-6-1365. PMID 3023421. 
  11. ^ KuKanich B (January 2008). "A review of selected systemic antifungal drugs for use in dogs and cats". Vetinary Medicine. 
  12. ^ Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (May 1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes". J. Clin. Invest. 71 (5): 1495–9. doi:10.1172/JCI110903. PMC 437014. PMID 6304148. 
  13. ^ 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. 
  14. ^ De Coster R, Wouters W, Bruynseels J (January 1996). "P450-dependent enzymes as targets for prostate cancer therapy". J. Steroid Biochem. Mol. Biol. 56 (1–6 Spec No): 133–43. doi:10.1016/0960-0760(95)00230-8. PMID 8603034. 
  15. ^ Eil C (August 1992). "Ketoconazole binds to the human androgen receptor". Horm. Metab. Res. 24 (8): 367–70. doi:10.1055/s-2007-1003337. PMID 1526623. 
  16. ^ Chin TW, Loeb M, Fong IW (August 1995). "Effects of an acidic beverage (Glass of Orange Juice) on absorption of ketoconazole". Antimicrobial Agents and Chemotherapy 39 (8): 1671–5. doi:10.1128/AAC.39.8.1671. PMC 162805. PMID 7486898. 
  17. ^ McElwee KJ, Shapiro JS (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Lett. 17 (6): 1–4. PMID 22735503. 
  18. ^ Hugo Perez BS (2004). "Ketocazole as an adjunct to finasteride in the treatment of androgenetic alopecia in men". Med. Hypotheses 62 (1): 112–5. doi:10.1016/S0306-9877(03)00264-0. PMID 14729013. 
  19. ^ Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE (1998). "Ketoconazole shampoo: effect of long-term use in androgenic alopecia". Dermatology (Basel) 196 (4): 474–7. doi:10.1159/000017954. PMID 9669136. 
  20. ^ 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". Int J Cosmet Sci 24 (5): 249–56. doi:10.1046/j.1467-2494.2002.00145.x. PMID 18498517. 
  21. ^ Khandpur S, Suman M, Reddy BS (August 2002). "Comparative efficacy of various treatment regimens for androgenetic alopecia in men". J. Dermatol. 29 (8): 489–98. PMID 12227482. 
  22. ^ Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy". Postgrad Med J 66 (773): 221–3. doi:10.1136/pgmj.66.773.221. PMC 2429473. PMID 2362890. 
  23. ^ 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". Gynecol. Endocrinol. 13 (3): 175–82. doi:10.3109/09513599909167552. PMID 10451809. 
  24. ^ Kazy Z, Puhó E, Czeizel AE (March 2005). "Population-based case-control study of oral ketoconazole treatment for birth outcomes". Congenit Anom (Kyoto) 45 (1): 5–8. doi:10.1111/j.1741-4520.2005.00053.x. PMID 15737124. 
  25. ^ 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. 
  26. ^ a b 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". J. Med. Chem. 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 Pharmacol. Appl. Skin Physiol. 15 (6): 434–41. doi:10.1159/000066452. PMID 12476017. 

External links[edit]