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Ketoconazole

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{{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 418697139 | 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 | image = Ketoconazole2.png | width = 200 | image2 = Ketoconazole 3D balls 1jin.png | width2 = 200

| tradename = Nizoral | Drugs.com = Monograph | MedlinePlus = a682816 | pregnancy_category = B3 (Au), C (United States) | legal_US = OTC | legal_status = POM (UK, oral formulation) | routes_of_administration = Oral, topical

| bioavailability = Variable | protein_bound = 84 to 99% | metabolism = Hepatic | elimination_half-life = Biphasic: | excretion = Biliary and renal

| CASNo_Ref =  checkY | CAS_number = 65277-42-1 | ATC_prefix = J02 | ATC_suffix = AB02 | ATC_supplemental = D01AC08 (WHO) G01AF11 (WHO) | PubChem = 456201 | DrugBank_Ref =  checkY | DrugBank = APRD00401 | ChemSpiderID_Ref =  checkY | ChemSpiderID = 401695 | UNII_Ref =  checkY | UNII = R9400W927I | KEGG_Ref =  checkY | KEGG = D00351 | ChEBI_Ref =  ☒N | ChEBI = 48336 | ChEMBL_Ref =  checkY | ChEMBL = 75

| C=26 | H=28 | Cl=2 | N=4 | O=4 | molecular_weight = 531.431 g/mol | smiles = O=C(N5CCN(c4ccc(OC[C@@H]1O[C@](OC1)(c2ccc(Cl)cc2Cl)Cn3ccnc3)cc4)CC5)C | InChI = 1/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 | InChIKey = XMAYWYJOQHXEEK-OZXSUGGEBE | StdInChI_Ref =  checkY | StdInChI = 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 | StdInChIKey_Ref =  checkY | StdInChIKey = XMAYWYJOQHXEEK-OZXSUGGESA-N }}

Ketoconazole (/[invalid input: 'icon']ˌkiːt[invalid input: 'ɵ']ˈkoʊnəzɒl/) is a synthetic antifungal 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 anti-dandruff shampoo, topical cream, and oral tablet, under the trademark name Nizoral by Ortho-McNeil Pharmaceutical in the United States, Australia and Canada, as Sebizole by Douglas Pharmaceuticals in Australia and New Zealand and as Ketomed in Latin America.[1] In Spain, products with ketoconazole as main agent include Ketoisdin gel (gel) and Fungarest (cream). In India, ketoconazole is sold as 'ketoZink' soap.

Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole have largely replaced ketoconazole 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.[2]

Medical uses

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. [3] [4]

Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.

The side-effects of ketoconazole are sometimes used to treat non-fungal problems. The decrease in testosterone caused by the drug makes it useful for treating prostate cancer and for preventing post-operative erections [5] following penile surgery. Another use is the suppression of glucocorticoid synthesis, where it is used in the treatment of Cushing's syndrome.[6] These side effects have also been studied for use in reducing depressive symptoms [7] and drug addiction;[8] however, it has not succeeded in either of these roles. [9] [10]

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

It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis in high dosages. Until recently, there were two human test cases on record (both during the treatment of Cushing's syndrome) [11] [12] and no adverse effects were reported, but this is not a broad enough data sample to draw any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.[13]

Hair loss

Some preliminary research suggests that ketoconazole shampoo may be beneficial in men suffering from androgenic alopecia. Support for this comes primarily from a single study in 1998 that compared ketoconazole 2% to the proven hair loss drug minoxidil 2% in men with androgenic alopecia.[14] In a sample of 27 men, "Hair density and size and proportion of anagen follicles were improved almost similarly by both ketoconazole and minoxidil regimens." While ketoconazole's possible mechanism of action in hair loss is still unclear, the study speculated that 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 that it may help to prevent hair loss by reducing inflammation from the fungus, in addition to having a direct anti-inflammatory effect. In this one study, men washed with ketoconazole 2% shampoo, used once every 2–4 days, leaving the shampoo on the scalp for 3–5 minutes before rinsing (as with the treatment of dandruff and seborrheic dermatitis).[14]

The researchers were guarded about the meaning of their results, saying that 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. Although no further research in humans has been undertaken, there was a study on ketoconazole in 2005 that supported the existence of a stimulatory effect on hair growth, this time in mice.[15]

Ketoconazole shampoo is only FDA approved for the treatment of dandruff and seborrheic dermatitis of the scalp, so while the question whether ketoconazole may possibly be useful as a hair loss remedy remains open, the FDA does not accept that there is enough evidence to endorse or market it as one to the general public.[16]

Mechanism of action

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). 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 3x/day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.[17] Ketoconazole 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.[18] 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.[19]

Susceptible fungi

Ketoconazole inhibits growth of dermatophytes and yeast species such as Candida albicans. The rise in the number of HIV/AIDS immune compromised 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 Genes (MDR)[20] 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

Nizoral 2% anti-dandruff shampoo (AU)

The chemical synthesis of ketoconazole begins with dichloroacetophenone:[21]

History

Ketoconazole was discovered in 1976 and released in 1981.[22] It followed griseofulvin as one of the first available oral treatments for fungal infections.

Veterinary uses

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.[23]

References

  1. ^ "Ketomed". Facultad de Medicina, Universidad Nacional de México. Retrieved 2011-05-27.
  2. ^ T W Chin, M Loeb, and I W Fong (1995). "Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole". Antimicrobial agents and chemotherapy. 39 (8): 1671–5. PMC 162805. PMID 7486898. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ MedlinePlus Medical Encyclopedia: Tinea versicolor
  4. ^ Tinea Versicolor
  5. ^ Evans, K. C. (2004). "Use of oral ketoconazole to prevent postoperative erections following penile surgery". International Journal of Impotence Research. 16 (4): 346–349. doi:10.1038/sj.ijir.3901160. PMID 14973533. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  6. ^ Loli, Paola (1986). "Use of ketoconazole in the treatment of Cushing's syndrome". Journal of Clinical Endocrinology & Metabolism. 63 (6): 1365–71. doi:10.1210/jcem-63-6-1365. PMID 3023421. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  7. ^ Wolkowitz, Owen M. (1999). "Treatment of depression with antiglucocorticoid drugs". Psychosomatic Medicine. 61 (5): 698–711. PMID 10511017. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  8. ^ Goeders, Nick E. (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  9. ^ Malison, Robert T. (1999). "Limited efficacy of ketoconazole in treatment-refractory major depression". Journal of Clinical Psychopharmacology. 19 (5): 466–470. doi:10.1097/00004714-199910000-00011. PMID 10505589. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  10. ^ Ward, Amie S. (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  11. ^ Amado, José Antonio (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  12. ^ Berwaerts, Joris (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  13. ^ Kazy, Zoltán (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  14. ^ a b Ketoconazole Shampoo: Effect of Long-Term Use in Androgenic Alopecia
  15. ^ Jiang J, Tsuboi R, Kojima Y, Ogawa H (2005). "Topical application of ketoconazole stimulates hair growth in C3H/HeN mice". J. Dermatol. 32 (4): 243–7. PMID 15863844. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Nizoral Shampoo as a Hair Loss Remedy?
  17. ^ Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ De Coster R, Wouters W, Bruynseels J (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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Eil C (1992). "Ketoconazole binds to the human androgen receptor". Horm. Metab. Res. 24 (8): 367–70. doi:10.1055/s-2007-1003337. PMID 1526623. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help); Unknown parameter |month= ignored (help)
  20. ^ MDR Gene: on Medical Dictionary Online
  21. ^ 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. {{cite journal}}: Italic or bold markup not allowed in: |journal= (help)
  22. ^ MedicineNet.com – ketoconazole (Nizoral, Extina, Xolegel, Kuric)
  23. ^ Ketoconazole for Your Pet at Petscriptions
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