Ketoconazole

Ketoconazole is a synthetic imidazole antifungal drug used primarily to

Ketoconazole
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 dermatitisof 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
(2R,4S)-(+)-ketoconazole (top)
the European Union, after concluding that the risk of serious liver injury
(2S,4R)-(−)-ketoconazole (bottom)
from systemic ketoconazole outweighs its benefits.[7] The oral Clinical data
formulation of ketoconazole was discontinued in Australia in 2013[8][9] Pronunciation /ˌkiːtoʊˈkoʊnəˌzoʊl, -zɒl/[1][2]
and in China in 2015.[10] Trade names Nizoral
AHFS/Drugs.com Monograph
MedlinePlus a682816
Contents License data EU EMA: by INN

Medical uses US FDA: Ketoconazole

Antifungal
Pregnancy AU: B3
Topical antifungal category
Systemic antifungal US: C (Risk not ruled out)
Antiandrogen and antiglucocorticoid
Routes of Oral (tablets), topical
Off-label uses
administration (cream, shampoo, solution)
Hair loss
Veterinary use ATC code J02AB02 (WHO) D01AC08
Side effects (WHO) G01AF11 (WHO)
Pharmacology Legal status
Resistance
Legal status UK: POM (Prescription only)
Pharmacokinetics
History US: OTC

Society and culture Pharmacokinetic data

Name
Bioavailability Oral: 37–97%[3]
See also
Protein binding 84 to 99%
References
Metabolism Extensive liver
Further reading
(predominantly oxidation, O-
External links
dealkylation)
Metabolites N-deacetyl ketoconazole

Medical uses Biological half-

life
Biphasic

Excretion Biliary (major) and renal[4]

Antifungal Identifiers
IUPAC name
Topical antifungal CAS Number 65277-42-1
Topically administered ketoconazole is usually prescribed for fungal PubChem CID 3823
infections of the skin and mucous membranes, such as athlete's foot,
IUPHAR/BPS 2568
ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea
versicolor.[11] Topical ketoconazole is also used as a treatment for DrugBank DB01026
dandruff (seborrheic dermatitis of the scalp) and for seborrheic ChemSpider 401695
dermatitis on other areas of the body, perhaps acting in these conditions
by suppressing levels of the fungus Malassezia furfur on the UNII R9400W927I
skin.[11][12][13] KEGG D00351
ChEBI CHEBI:48336
Systemic antifungal
ChEMBL CHEMBL75
Ketoconazole has activity against many kinds of fungi that may cause
human disease, such as Candida, Histoplasma, Coccidioides, and PDB ligand KTN (PDBe, RCSB PDB)
Blastomyces (although it is not active against Aspergillus).[14] First ECHA InfoCard 100.059.680
synthesized in 1977,[11] ketoconazole was the first orally-active azole
Chemical and physical data
antifungal medication.[14] However, ketoconazole has largely been
replaced as a first-line systemic antifungal medication by other azole Formula C26H28Cl2N4O4
antifungal agents, such as itraconazole, because of ketoconazole's Molar mass 531.431 g/mol
greater toxicity, poorer absorption, and more limited spectrum of 3D model Interactive image
activity.[14][15] (JSmol)
Chirality Racemic mixture[4][5]
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the
[16]
treatment of superficial and deep fungal infections. SMILES
InChI
(verify)
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 sterolergosterol 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
suchas 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
A bottle of Ketoconazole shampoo
[16]
indications, especially in those that are benign such as hirsutism.

Off-label uses
Hair loss
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]

[22][23] or in
Limited clinical studies suggest ketoconazole shampoo used either alone
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
gery patients.[25]
temporarily reducing erectile function in postoperative penile sur

Veterinary use
Ketoconazole is also sometimes prescribed by veterinarians for use on pets, often as
Nizoral (ketoconazole) 2% shampoo
[26]
unflavored tablets that may need to be cut to smaller size for correct dosage.

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
[29]
in Europe failed to show a risk to infants of mothers receiving ketoconazole.

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
[30]
formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.

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 greateraffinity 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 withmiconazole, has been found to act as anantagonist 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]

Ketoconazole has been found to inhibit the activity of the cation channelTRPM5.[36]

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
.[37][38]
normally cross-resistant to all members of the azole family

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.[39]
Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.

History
Ketoconazole was discovered in 1976 at Janssen Pharmaceutica.[40] 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.[41] Oral ketoconazole has been
replaced with oral itraconazole for many mycoses.[41]

Society and culture

Name
Ketoconazole is the drug's INN, USAN, BAN, and JAN.[42][43]

See also
Abiraterone acetate
Aminoglutethimide
Levoketoconazole

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

External links
PubPK | Ketoconazole pharmacokinetics
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.
Janssen Pharmaceutica | Nizoral

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