Ketoconazole
Ketoconazole
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. B3 (AU) C (US)
Legal status POM (UK) OTC (US)
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
Chemical data
Formula C26H28Cl2N4O4 
Mol. mass 531.431 g/mol
 YesY (what is this?)  (verify)

Ketoconazole (pron.: /ˌkiːtɵˈkoʊnəzɒl/) is a synthetic antifungal and antiandrogenic drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an antidandruff shampoo, topical cream, and oral tablet.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole are sometimes preferred for internal use.[citation needed] Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption when taken orally. Absorption can be increased by taking it with an acidic beverage, such as cola.[1]

Contents

Medical uses [edit]

Antifungal [edit]

Ketoconazole is usually prescribed for topical infections such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), and jock itch. The over-the-counter shampoo version can also be used as a body wash for the treatment of tinea versicolor.[2][3] Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.

The side effects of ketoconazole are sometimes used to treat nonfungal problems. The decrease in testosterone caused by the drug makes it useful for treating prostate cancer and for preventing postoperative erections[4] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's syndrome.[5] These side effects have also been studied for use in reducing depressive symptoms [6] and drug addiction;[7] however, it has not succeeded in either of these roles.[8][9]

Ketoconazole is also used in combination with other drugs such as zinc pyrithione in rinse-off products. The antidandruff shampoo is designed for people who have a more serious case of dandruff where symptoms include, but are not limited to constant, nonstop flaking, and severe itchiness.

It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis in high dosages. Recently, two human test cases (both during the treatment of Cushing's syndrome)[10][11] were reported to have no adverse effects, 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.[12]

Hair loss [edit]

Nizoral (ketoconazole) 2% shampoo

Preliminary research suggests ketoconazole shampoo may be beneficial in men suffering from androgenic alopecia. Support for this comes from a study in 1998 that compared ketoconazole 2% to the proven hair loss drug minoxidil 2% in men with androgenic alopecia.[13] In a sample of 27 men, "[h]air density and size and proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens." The men washed with ketoconazole 2% shampoo once every two to four days, leaving the shampoo on the scalp for three to five minutes before rinsing (as with the treatment of dandruff and seborrheic dermatitis).[13] While ketoconazole's mechanism of action in hair loss is still unclear, the researchers in the 1998 study postulated both hormones and the immune system may act synergistically to cause injury to the hair follicle. Since ketoconazole effectively treats the Malassezia fungus that commonly inhabits the scalp, the researchers hypothesized it may prevent hair loss by reducing inflammation from the fungus, in addition to having a direct anti-inflammatory effect. The researchers were guarded about the meaning of their results, saying more rigorous studies on larger groups of men should be done to confirm the findings, both to evaluate the ideal dosage and formulation, and to assess the desirability of routine treatment in this condition.

In 2002, a study of 150 men at the University of Liège in Belgium found 1% ketoconazole shampoo used 2-3 times a week for six months increased hair shaft diameter by 5.4%, increased anagen hair by 4.9%, and decreased hair shedding by 17.3%, although it found no effect on hair density.[14] An additional 2002 study in men with androgenetic alopecia found that a regimen of ketoconazole and finasteride was more effective than finasteride alone in treating male pattern baldness.[15] In 2005, a study of ketoconazole in mice also found support the existence of a stimulatory effect on hair growth.[16]

Although ketoconazole may be useful as a hair loss treatment, the shampoo is currently only FDA-approved for the treatment of dandruff and seborrheic dermatitis of the scalp.

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.[17]

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).[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.[19] It produces this effect through inhibition of cytochrome P450 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.[20] Second, ketoconazole is an androgen receptor antagonist, competing with androgens such as testosterone and DHT for androgen receptor binding. This effect is thought to be quite weak, even with high oral doses of ketoconazole.[21]

Susceptible fungi [edit]

Ketoconazole inhibits growth of dermatophytes and yeast species such as Candida albicans. The rise in the number of HIV/AIDS immunocompromised patients has led to an increase in the frequency and significance of opportunistic fungal infections. Resistance to ketoconazole has been observed in a number of clinical fungal isolates, including C. 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[22] 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.

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. [23]

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 benoylic 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 and released in 1981.[24] It followed griseofulvin as one of the first available oral treatments for fungal infections.

Brand names [edit]

It is marketed under the trademark name Nizoral by Ortho-McNeil Pharmaceutical in the United States, Australia, Canada and UK, as Sebizole by Douglas Pharmaceuticals in Australia and New Zealand and as Ketomed in Latin America.[25] In Spain, products with ketoconazole as main agent include Ketoisdin gel and Fungarest (cream). In India, ketoconazole is sold as 'keton' (tablets, soap and cream) by Green Apple Lifesciences Limited and as ketomac Shampoo manufactured by Torque Pharmaceuticals.

References [edit]

  1. ^ 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. PMC 162805. PMID 7486898. 
  2. ^ MedlinePlus Medical Encyclopedia: Tinea versicolor
  3. ^ Tinea Versicolor
  4. ^ Evans, K. C.; Peterson AC, Ruiz HE, Costabile RA (August 2004). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research 16 (4): 346–9. doi:10.1038/sj.ijir.3901160. PMID 14973533. 
  5. ^ 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. 
  6. ^ Wolkowitz, OM; Reus VI (September 1999). "Treatment of depression with antiglucocorticoid drugs". Psychosomatic Medicine 61 (5): 698–711. PMID 10511017. 
  7. ^ Goeders, NE; Peltier RL, Guerin GF (December 1998). "Ketoconazole reduces low dose cocaine self-administration in rats". Drug and Alcohol Dependence 53 (1): 67–77. doi:10.1016/S0376-8716(98)00108-2. PMID 10933341. 
  8. ^ Malison, RT; Anand A, Pelton GH, Kirwin P, Carpenter L, McDougle CJ, Heninger GR, Price LH (October 1999). "Limited efficacy of ketoconazole in treatment-refractory major depression". Journal of Clinical Psychopharmacology 19 (5): 466–70. doi:10.1097/00004714-199910000-00011. PMID 10505589. 
  9. ^ Ward, AS; Collins ED, Haney M, Foltin RW, Fischman MW (November 1998). "Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans". Behavioural Pharmacology 9 (7): 577–86. doi:10.1097/00008877-199811000-00013. PMID 9862083. 
  10. ^ Amado, José Antonio; Carlos Pesquera, Eva M. Gonzalez, Macarena Otero, Julio Freijanes, and Angel Alvarez (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 2429473. PMID 2362890. 
  11. ^ Berwaerts, Joris; Johan Verhelst, Charles Mahler and Roger Abs (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. 
  12. ^ Kazy, Zoltán; Erzsébet Puhó ; Andrew E. Czeizel (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. 
  13. ^ a b Ketoconazole Shampoo: Effect of Long-Term Use in Androgenic Alopecia
  14. ^ 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. 
  15. ^ http://www.ncbi.nlm.nih.gov/pubmed/12227482
  16. ^ Jiang J, Tsuboi R, Kojima Y, Ogawa H (April 2005). "Topical application of ketoconazole stimulates hair growth in C3H/HeN mice". J. Dermatol. 32 (4): 243–7. PMID 15863844. 
  17. ^ Ketoconazole for Your Pet at Petscriptions
  18. ^ Loose, D S; Kan, P B; Hirst, M A; Marcus, R A; Feldman, D (1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes". Journal of Clinical Investigation 71 (5): 1495–9. doi:10.1172/JCI110903. PMC 437014. PMID 6304148. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ MDR Gene: on Medical Dictionary Online
  23. ^ Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. (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. 
  24. ^ Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem, J. (1 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): 1003–1005. doi:10.1021/jm00194a023. 
  25. ^ "Ketomed". Facultad de Medicina, Universidad Nacional de México. Retrieved 2011-05-27. 


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This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Ketoconazole".