Ketoconazole

Structural formula
	Ketoconazole, a 1: 1 mixture of the stereoisomers (2 S , 4 R ) -ketoconazole (top) and (2 R , 4 S ) -ketoconazole (bottom)
General
Non-proprietary name	Ketoconazole
other names	(2 RS , 4 SR ) -1- (4- {4 - [- 2- (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} piperazin-1-yl) ethanone ( IUPAC ); (±) - cis -1-Acetyl-4- {4- [ cis -2- (2,4-dichlorophenyl) -2- (1-imidazolylmethyl) -1,3-dioxolan-4-ylmethoxy] phenyl} piperazine; Ketoconazolum ( Latin );
Molecular formula	C 26 H 28 Cl 2 N 4 O 4
Brief description	white to almost white powder
External identifiers / databases
EC number	265-667-4
ECHA InfoCard	100.059.680
PubChem	3823
ChemSpider	3691
DrugBank	DB01026
Wikidata	Q407883
Drug information
ATC code	J02 AB02 ; D01 AC08 ; G01 AF11 ;
Drug class	Antifungal agent
Mechanism of action	Inhibition of the biosynthesis of ergosterol in mushrooms
properties
Molar mass	531.43 g · mol -1
Physical state	firmly
Melting point	146 ° C
solubility	practically insoluble in water, slightly soluble in dichloromethane , soluble in methanol , slightly soluble in ethanol
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
H and P phrases	H: 301-360F-373-410
	P: 201-273-301 + 310-308 + 313-501
Toxicological data	166 mg kg −1 ( LD 50 , rat , oral ) ; 86 mg kg −1 ( LD 50 , rat , iv ) ; 618 mg kg −1 ( LD 50 , mouse , oral ) ; 32 mg kg −1 ( LD 50 , mouse , iv ) ;
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ketoconazole is a drug from the group of imidazoles that is used to prevent and treat fungal diseases of the skin.

history

Ketoconazole was patented by Janssen-Cilag in 1978 and marketed in the early 1980s. It was the first oral antifungal drug .

application

The drug is especially used in people with an immune system disease such as AIDS or infections due to autoimmune diseases. Examples of diseases that can be treated with the drug are seborrheic eczema or pityriasis versicolor (bran fungus).

Ketoconazole, for example, in anti- dandruff - shampoos used. There are different strength doses of the remedy. The shampoo can be used like a normal shampoo if it is rinsed out thoroughly after use. To be on the safe side, it should not be used during pregnancy, as animal experiments showed damage to the fruit at high doses.

Ketoconazole is only available from pharmacies ; Pharmaceutical forms for systemic use ( tablets ) also require a prescription in most countries .

Ketoconazole is also used for Cushing's disease . It inhibits the production of cortisol and is used when surgical measures are not possible.

Mode of action

Ketoconazole prevents the production of ergosterol , which is the main component of the pathogen's cell membrane . The mode of action is based on the inhibition of cytochrome P450- dependent enzymes, which explains both the hepatotoxicity and the use in Cushing's disease . The synthesis of adrenal hormones (e.g. cortisol ) requires enzymes that are dependent on cytochrome P450 in several places.

Treatable pathogens

Ketoconazole prevents the growth of dermatophytes and yeasts such as Candida albicans . Resistance to ketoconazole is known in some Candida albicans strains.

Side effects

The European Medicines Agency wants to ban the oral ketoconazole because of the severe liver damage. In contrast, the FDA only issues warnings about using oral ketoconazole.

Oral ketoconazole is a potent inhibitor of cortisol synthesis due to its ability to inhibit cytochrome P450 enzymes in the adrenal gland . Ketoconazole also has direct effects on corticotropic tumor cells in patients with Cushing's syndrome. Oral ketoconazole is contraindicated in patients with acute or chronic liver disease or if liver enzyme levels are more than twice the upper limit of normal at the start of treatment. Treatment with it must not be continued if symptoms of hepatitis are present or liver enzyme levels are three times the upper limit of normal.

The mechanism of damage to the liver as a result of taking ketoconazole is not fully understood. Due to the risk of hepatotoxicity, marketing authorization for oral ketoconazole as an antifungal agent was suspended in October 2013.

Because of its side effects, ketoconazole is increasingly being replaced by newer fungicides such as fluconazole and / or itraconazole .

Chemical properties

Ketoconazole is a white to yellowish powder with a melting temperature of 146 ° C. It is highly lipophilic and very sparingly soluble in water. It is an imidazole derivative and generally belongs to the group of azole fungicides .

Stereoisomerism

From the structural formula of ketoconazole it can be seen that the molecule on the 1,3-dioxolane ring contains two stereocenters in the 2- and 4-position. Theoretically there are four stereoisomers : The (2 S , 4 R ) form and the mirror image (2 R , 4 S ) form as well as the (2 S , 4 S ) form and the mirror image (2 R , 4 R ) shape. As a drug , a is a racemate (1: 1 mixture) of the mutually enantiomeric (2 S , 4 R ) -form and the (2 R , 4 S ) -form used, also known as racemic cis -form or (±) - cis Shape is called.

The (2 R , 4 R ) form and the (2 S , 4 S ) form have no practical significance.

Trade names

Monopreparations

Nizoral (CH, D), Terzolin (D), Ket (D), Ketozolin (D), Fungoral (A), Lur (CH), Ninazol (Th)

Individual evidence

↑ ^a ^b European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.
↑ Entry on ketoconazole in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ ^a ^b Entry on ketoconazole in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .
↑ Entry on ketoconazole in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016. Manufacturers or distributors can expand the harmonized classification and labeling .
↑ ^a ^b ^c ^d ^e Entry on ketoconazole. In: Römpp Online . Georg Thieme Verlag, accessed on January 8, 2015.
↑ ABDA database.
↑ DS Loose, PB Kan, MA Hirst, RA Marcus and D. Feldman: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest. 1983; 71 (5): pp. 1495-1499. PMC 437014 (free full text) doi: 10.1172 / JCI110903 .
^ European Medicines Agency recommends suspension of marketing authorizations for oral ketoconazole
↑ Information letter on ketoconazole 200 mg tablets (Nizoral® tablets) (PDF; 72 kB) Drug Commission of the German Medical Association of August 22, 2013.
↑ FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems
↑ ^a ^b HRA Pharma Germany: Rote-Hand-Brief on Ketoconazole HRA® (Ketoconazole): Risk of hepatotoxicity. (PDF) Medicines Commission of the German Medical Association, accessed on May 25, 2015 .

[Ph._Eur._5-1] European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.

[ChemIDplus-2] Entry on ketoconazole in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[GESTIS-3] Entry on ketoconazole in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .

[CLP_100.059.680-4] Entry on ketoconazole in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016. Manufacturers or distributors can expand the harmonized classification and labeling .

[roempp-5] Entry on ketoconazole. In: Römpp Online . Georg Thieme Verlag, accessed on January 8, 2015.

[6] ABDA database.

[7] DS Loose, PB Kan, MA Hirst, RA Marcus and D. Feldman: Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes. J Clin Invest. 1983; 71 (5): pp. 1495-1499. PMC 437014 (free full text) doi: 10.1172 / JCI110903 .

[8] European Medicines Agency recommends suspension of marketing authorizations for oral ketoconazole

[9] Information letter on ketoconazole 200 mg tablets (Nizoral® tablets) (PDF; 72 kB) Drug Commission of the German Medical Association of August 22, 2013.

[10] FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems

[HRA-11] HRA Pharma Germany: Rote-Hand-Brief on Ketoconazole HRA® (Ketoconazole): Risk of hepatotoxicity. (PDF) Medicines Commission of the German Medical Association, accessed on May 25, 2015 .