CYP3A4; CYP24A1; ergosterol synthesis

(+)-Ketoconazole ((+)-R 41400), an imidazole anti-fungal agent, has often produced features of androgen deficiency including decreased libido, gynecomastia, impotence, oligospermia, and decreased testosterone levels, in men being treated for chronic mycotic infections. Based on these potent effects on gonadal function in vivo as well as previous work in vitro demonstrating affinity of ketoconazole for receptor proteins for glucocorticoids and 1,25(OH)2 vitamin D3 and for sex steroid binding globulin (SSBG), the binding of ketoconazole to human androgen receptors (AR) in vitro was also examined. Ketoconazole competition with [3H]methyltrienolone (R1881) for androgen binding sites in dispersed, intact cultured human skin fibroblasts was determined at 22 degrees C. Fifty percent displacement of [3H]R1881 binding to AR was achieved by 6.4 +/- 1.8 (SE) x 10(-5) M ketoconazole. Additional binding studies performed with ketoconazole in the presence of increasing amounts of [3H]R1881 showed that the interaction of ketoconazole with AR was competitive when the data were analyzed by the Scatchard method. It should be noted, however, that the dose of ketoconazole required for 50% occupancy of the androgen receptor is not likely to be achieved in vivo, at least in plasma. Finally, androgen binding studies performed with other imidazoles, such as clotrimazole, miconazole, and fluconozole, revealed that in this class of compounds only ketoconazole appears to interact with the androgen receptor. Ketoconazole appears to be the first example of a non-steroidal compound which binds competitively to both SSBG and multiple steroid hormone receptors, suggesting that the ligand binding sites of these proteins share some features in common.[1]

The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.[2]

Absorption, Distribution and Excretion
Ketoconazole requires an acidic environment to dissolve in water. Its solubility gradually decreases above pH 3, with only about 10% of the drug dissolving within 1 hour. Below pH 3, solubility reaches 85% within 5 minutes and complete dissolution within 30 minutes. A single oral dose of 200 mg ketoconazole results in a peak plasma concentration (Cmax) of 2.5–3 μg/mL and a time to peak concentration (Tmax) of 1–4 hours. Co-administration with food generally increases Cmax and delays Tmax, but the impact on AUC is inconsistent in the literature, and AUC may decrease slightly. The bioavailability of ketoconazole is reported to be 76%. Only 2–4% of ketoconazole is excreted unchanged in the urine. Over 95% of ketoconazole is eliminated by hepatic metabolism. The estimated volume of distribution of ketoconazole is 25.41 L or 0.36 L/kg. It is widely distributed in various tissues, reaching effective concentrations in skin, tendons, tears, and saliva. The concentration in vaginal tissues is 2.4 times lower than in plasma. Ketoconazole has extremely low permeability in the central nervous system, bones, and semen. Animal studies have shown that ketoconazole can enter breast milk and cross the placenta. The estimated clearance of ketoconazole is 8.66 L/h. Ketoconazole is rapidly absorbed from the gastrointestinal tract. After oral administration, ketoconazole dissolves in gastric juice and is converted to hydrochloride before being absorbed by the stomach. The effect of food on the rate and extent of gastrointestinal absorption of ketoconazole is not well understood. Some clinicians have reported that taking ketoconazole on an empty stomach results in higher plasma drug concentrations than taking it with food. However, manufacturers indicate that taking it with food improves the absorption rate of ketoconazole and makes plasma drug concentrations more stable. Manufacturers believe that food improves its absorption rate by increasing the rate and/or extent of ketoconazole's dissolution (e.g., by increasing bile secretion) or delaying gastric emptying. Ketoconazole is a weak dibasic drug and therefore requires an acidic environment to dissolve and be absorbed. The bioavailability of oral ketoconazole depends on the pH of the gastric contents; elevated pH leads to reduced drug absorption. Reduced ketoconazole bioavailability has been reported in patients with acquired immunodeficiency syndrome (AIDS), possibly due to disease-related gastric acid deficiency. Concomitant administration of dilute hydrochloric acid solution can restore normal drug absorption in these patients. Drinking acidic beverages may increase the bioavailability of oral ketoconazole in some patients with gastric acid deficiency. For more complete data on the absorption, distribution, and excretion of ketoconazole (19 items), please visit the HSDB records page. Metabolites/Metabolites: The major metabolite of ketoconazole appears to be M2, the final product of the partial oxidation of imidazole. CYP3A4 is known to be a major participant in this reaction, with CYP2D6 also contributing. Other metabolites produced by the CYP3A4-mediated partial oxidation of imidazole include M3, M4, and M5. Ketoconazole can also undergo N-deacetylation to generate M14, alkyl oxidation to generate M7, N-oxidation to generate M13, aromatic hydroxylation to generate M8, or hydroxylation to generate M9. M9 can further undergo hydroxylation to generate M12, N-dealkylation to generate M10, followed by N-dealkylation to generate M15, or form an imine ion. Currently, no active metabolites are known, but the oxidative metabolites of M14 are associated with cytotoxicity. Ketoconazole is partially metabolized in the liver to several inactive metabolites via metabolic pathways including oxidation and degradation of the imidazole and piperazine rings, oxidative dealkylation, and aromatic hydroxylation. The elimination of ketoconazole is biphasic, with an initial phase half-life of 2 hours and a terminal half-life of 8 hours. The plasma concentration of ketoconazole decreases biphasically, with an initial phase half-life of approximately 2 hours and a terminal phase half-life of approximately 8 hours.
Plasma elimination is biphasic, with a half-life of 2 hours in the first 10 hours and 8 hours thereafter.

Toxicity Summary
Identification and Use: Ketoconazole is an antifungal drug. Human Exposure and Toxicity: Transient increases in serum AST, ALT, and alkaline phosphatase levels may occur during ketoconazole treatment. Severe hepatotoxicity, including fatal cases and cases requiring liver transplantation, has been reported in patients receiving oral ketoconazole. Hepatotoxicity can manifest as hepatocellular (most cases), cholestatic, or mixed damage. While ketoconazole-induced hepatotoxicity is usually reversible upon discontinuation, recovery can take months and, in rare cases, can lead to death. Symptomatic hepatotoxicity typically occurs within the first few months of ketoconazole treatment, but can sometimes occur within the first week. Some patients with ketoconazole-induced hepatotoxicity have no apparent risk factors for liver disease. Severe hepatotoxicity has been reported in patients receiving short-term high-dose oral ketoconazole as well as long-term low-dose oral ketoconazole. Many reported cases of hepatotoxicity have occurred in patients receiving this drug for onychomycosis (fungal nail infection) or for chronic refractory dermatophyte infections. Ketoconazole-induced hepatitis has been reported in some children. Ketoconazole at commonly used doses (200-400 mg daily) has been reported to transiently (lasting 2-12 hours) inhibit testosterone synthesis in the testes. Compensatory increases in serum luteinizing hormone (LH) concentrations may occur. A more persistent effect on testosterone synthesis has been reported at doses of 800-1200 mg daily; in a study of men receiving these higher doses, approximately 30% of patients in the 800 mg daily group and all patients in the 1200 mg daily group maintained serum testosterone concentrations below normal levels (below 300 ng/dL) throughout the day. Oligospermia, a condition characterized by reduced sperm count, often presents with decreased libido and impotence in these men, while azoospermia is rare. The drug appears to directly inhibit the synthesis of adrenal steroids and testosterone both in vitro and in vivo. The primary mechanism by which ketoconazole inhibits steroid synthesis appears to be through blocking multiple P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain lyase). Overall, these results indicate that many commonly used azole fungicides have endocrine-disrupting effects in vivo, although their mechanisms of action differ. Ketoconazole is known to have multiple endocrine-disrupting effects in humans. Animal studies: Oral administration resulted in sedation, rigidity, ataxia, tremors, convulsions, and, at doses >320 mg/kg, loss of righting reflex before death in mice, rats, and guinea pigs. Toxicity was also observed in dogs. Diarrhea and vomiting occurred at doses exceeding 80 mg/kg. Ketoconazole has been administered orally (gavage) and intravenously to mice, rats, guinea pigs, and dogs. Intravenous administration resulted in toxicity in rats, mice, and guinea pigs manifesting as convulsions, convulsions, and respiratory distress; mice, guinea pigs, and dogs showed loss of righting reflex before death. In dogs, toxicity was also manifested by licking and convulsions. In rats, except for a decrease in overall tumor incidence in female rats in the high-dose group, there were no significant differences in overall tumor incidence and type between the treatment and control groups. In rat developmental studies, the stillbirth rate in the 40 mg/kg dose group increased from 0.5% in the control group to 32.7%, and cannibalism was observed in both litters. In mice, sperm count was significantly reduced. Motility and density of the epididymal tail were observed. Fertility in ketoconazole-treated mice decreased sharply (50% were negative). Total protein and sialic acid content in the testes, epididymis, seminal vesicles, and ventral prostate were significantly reduced. Cholesterol content in the testes increased, while fructose content in the seminal vesicles decreased significantly. Ketoconazole treatment altered the biochemical environment of the reproductive tract. In rabbits, high doses (40 mg/kg/day) of ketoconazole exhibited maternal toxicity, embryotoxicity, and teratogenicity. Ketoconazole did not show any mutagenicity when assessed using the dominant lethal mutagenicity test or the Ames Salmonella microsomal activation test. Ecotoxicity studies: Ketoconazole induces the expression of CYP1A and CYP3A in rainbow trout. However, the most significant effect of ketoconazole is a 60% to 90% reduction in CYP3A catalytic activity in rainbow trout and killifish.

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Hepatotoxicity
In patients taking oral ketoconazole, 4% to 20% experience mild and transient elevations in liver enzymes. These abnormalities are usually transient and asymptomatic, rarely requiring dose adjustment or discontinuation. Clinical hepatotoxicity caused by ketoconazole is described in detail in the literature, with an estimated incidence of 1/2000 to 1/15000. Liver injury usually presents as acute hepatitis-like manifestations 1 to 6 months after the start of treatment. Although most cases present with hepatocellular damage, cholestatic forms have also been reported. Rash, fever, eosinophilia, and autoantibody formation are rare. Recovery after discontinuation may be delayed, usually requiring 1 to 3 months. Severe cases may result in acute liver failure, death, or the need for emergency liver transplantation. Related descriptions exist.
Probability Score: A (Etiology of clinically established liver injury).

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Impact during pregnancy and lactation
◉ Overview of medication use during lactation
Due to limited experience with the use of ketoconazole or levoketoconazole during lactation, and their potential to inhibit liver enzymes and cause hepatotoxicity, alternative medications are recommended as a first choice. Manufacturers advise mothers taking ketoconazole or levoketoconazole to avoid breastfeeding during treatment and for one day after the last dose.
The risk to a breastfeeding infant is minimal or nonexistent when the mother uses ketoconazole shampoo or applies it topically to the skin. However, breastfeeding mothers should avoid topical application to the breasts or nipples, as the infant may ingest it orally, and safer alternatives are available. Water-soluble creams or gels should only be applied to the breasts, as ointments may expose the infant to high concentrations of mineral oil through the nipple. Licking.
◉ Effects on breastfed infants
A mother administered 200 mg of ketoconazole orally for 10 days, and no adverse reactions were observed in her 1-month-old breastfed infant.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding
Approximately 84% of ketoconazole is bound to plasma albumin, and another 15% is bound to blood cells, for a total plasma binding rate of 99%.

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Interactions
Since gastric acid is essential for the dissolution and absorption of ketoconazole, concomitant use of drugs that reduce gastric acid secretion or increase gastric pH (e.g., antacids, anticholinergics, histamine H2 receptor antagonists, proton pump inhibitors, sucralfate) may reduce ketoconazole absorption, leading to decreased plasma concentrations. Antifungal drug concentrations. Concomitant use of antacids, anticholinergics, histamine H2 receptor antagonists, proton pump inhibitors (e.g., omeprazole, lanoprazole), or sucralfate in patients receiving ketoconazole is not recommended.
Elevated plasma digoxin concentrations have been reported in patients receiving ketoconazole. While it is unclear whether concomitant use of ketoconazole contributes to these elevations, digoxin concentrations in patients receiving this antifungal medication should be closely monitored.
Like other imidazole derivatives, ketoconazole may enhance the anticoagulant effect of coumarin anticoagulants. When ketoconazole is used concomitantly with these medications, anticoagulation should be carefully monitored, and the anticoagulant dose adjusted accordingly.
Concomitant use of mefloquine (500 mg single dose) and ketoconazole (400 mg) in healthy adults, with once-daily (10-day) administration of ketoconazole, increased the mean peak plasma concentration and AUC of mefloquine by 64% and 79%, respectively, and prolonged the mean elimination half-life of mefloquine from 322 hours to 448 hours. Due to the risk of potentially fatal QTc interval prolongation, the manufacturer of mefluquine states that ketoconazole should not be used concurrently with mefluquine, nor should it be used within 15 weeks of the last dose of mefluquine. For more complete data on ketoconazole interactions (51 items in total), please visit the HSDB record page. Non-human toxicity values: Rat oral LD50: 166 mg/kg; Rat intravenous LD50: 86 mg/kg; Mouse oral LD50: 618 mg/kg; Mouse intravenous LD50: 41,500 ug/kg; Dog oral LD50: 178 mg/kg

[1]. Eil C. Ketoconazole binds to the human androgen receptor. Horm Metab Res. 1992 Aug;24(8):367-70.

[2]. Effect of ketoconazole, a cytochrome P450 inhibitor, on the efficacy of quinine and halofantrine against Schistosoma mansoni in mice. Korean J Parasitol. 2013 Apr;51(2):165-75.

Therapeutic Uses
Antifungal Drugs Ketoconazole tablets should only be used when other effective antifungal therapies are ineffective or intolerable to the patient, and the potential benefit outweighs the potential risk. Ketoconazole tablets (Nizoral) are indicated for the treatment of the following systemic fungal infections, especially in patients who have not responded to or are intolerant of other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole tablets should not be used for fungal meningitis because it has poor penetration into the cerebrospinal fluid. /US Product Label Includes/ Oral ketoconazole has been used for the palliative treatment of Cushing's syndrome (hypercortisolemia), including hyperadrenocorticism associated with adrenal or pituitary adenomas or ectopic adrenocorticotropic hormone-secreting tumors. Based on its endocrine effects, this drug has been used to treat advanced prostate cancer. The safety and efficacy of ketoconazole for these two indications have not been established. Oral ketoconazole has also been used to treat hypercalcemia in patients with sarcoidosis, as well as tuberculosis-associated hypercalcemia and idiopathic infantile hypercalcemia and hypercalciuria. /Not included on US product label/
Ketoconazole has been used to treat sporotrichosis caused by Sporothrix schenckii; however, it is not recommended due to its poor efficacy and more adverse reactions than some other azole drugs. Oral itraconazole is considered the first-line treatment for cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis, and can also be used as a follow-up treatment for more severe infections after effective treatment with intravenous amphotericin B. /Not included on US product label/
For more complete data on the therapeutic uses of ketoconazole (18 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Ketoconazole tablets should only be used when other effective antifungal therapies are unavailable or intolerable, and the potential benefits outweigh the potential risks. Hepatotoxicity: Serious hepatotoxicity, including cases of death or requiring liver transplantation, has been reported with oral ketoconazole. Some patients do not have obvious risk factors for liver disease. Patients receiving this medication should be informed of the risks by their physician and closely monitored. QT Interval Prolongation and Drug Interactions Leading to QT Interval Prolongation: Ketoconazole is contraindicated with the following drugs: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong the QT interval, sometimes even leading to life-threatening ventricular arrhythmias such as torsades de pointes. Transient increases in serum AST, ALT, and alkaline phosphatase levels may occur during ketoconazole treatment. Serious hepatotoxicity, including cases of death or requiring liver transplantation, has been reported in patients receiving oral ketoconazole. Hepatotoxicity can manifest as hepatocellular (in most cases), cholestatic, or mixed damage. Although ketoconazole-induced hepatotoxicity is usually reversible upon discontinuation, recovery can take months and, in rare cases, can lead to death. Symptomatic hepatotoxicity typically occurs within the first few months of ketoconazole treatment, but can sometimes occur within the first week. Some patients with ketoconazole-induced hepatotoxicity have no apparent risk factors for liver disease. Severe hepatotoxicity has been reported in patients taking high-dose oral ketoconazole for short periods and low-dose oral ketoconazole for long periods. Many reported cases of hepatotoxicity have occurred in patients receiving this drug to treat onychomycosis (tinea unguium) or chronic refractory dermatophyte infections. Ketoconazole-induced hepatitis has been reported in some children. Ketoconazole tablets are contraindicated for use with several CYP3A4 substrates, such as dofetilide, quinidine, cisapride, and pimozide. Concomitant use with ketoconazole can lead to increased plasma concentrations of these drugs and may increase or prolong therapeutic effects and adverse reactions, potentially resulting in serious adverse events. For example, elevated plasma concentrations of certain such drugs can lead to QT interval prolongation, which can sometimes result in life-threatening ventricular arrhythmias, including torsades de pointes (a potentially fatal arrhythmia). In addition, the following drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine), irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisodipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin, and colchicine. Ketoconazole tablets are contraindicated in patients with acute or chronic liver disease. For more complete data on drug warnings for ketoconazole (46 in total), please visit the HSDB records page.

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Pharmacodynamics
Ketoconazole, like other azole antifungal drugs, is a bacteriostatic agent that inhibits the growth of fungal cells, thereby preventing the growth and spread of fungi in the body.

C26H28N4O4CL2

531.43092

530.148

142128-59-4

Ketoconazole;65277-42-1;(-)-Ketoconazole;142128-57-2

456201

White to off-white solid powder

4.3

0

6

7

36

735

2

ClC(C=C1)=CC(Cl)=C1[C@@]2(CN3C=CN=C3)OC[C@H](COC4=CC=C(N5CCN(C(C)=O)CC5)C=C4)O2

XMAYWYJOQHXEEK-OZXSUGGESA-N

InChI=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

1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone

ketoconazole; (+)-Ketoconazole; 65277-42-1; 142128-59-4; Xolegel; (2R,4S)-ketoconazole; Kuric; MFCD00058579;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~33.33 mg/mL (~62.72 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)