Which Enzymes Are Inhibited By Ketoconazole?

Ketoconazole is an antifungal agent that inhibits the synthesis of ergosterol in fungal cell wall membranes and enzymes involved in steroid and androgen production. It also exerts inhibitory effects on the cytochrome P450 enzyme CYP3A4, increasing plasma concentrations of drugs such as cyclosporine A. The antifungic effect of ketoconazole is due to the inhibition of the cytochrome P450 enzyme lanosterol C-14-demethylase.

Ketoconazole’s antifungal effect is due to its interaction with 14-α-sterol demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Like all azole antifungal agents, ketoconazole works principally by inhibition of cytochrome P450 14α-demethylase (P45014DM), an enzyme in the sterol biosynthesis pathway that leads from lanosterol to ergosterol.

In humans, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 17 C17-20lyase in the adrenal glands, resulting in a rapid and marked reduction in adrenal steroid production. It also competitively inhibits the activities of steroid 17α-hydroxylase and C17-20lyase in rat and human testes, 16α-hydroxylase in human testes, and CYP3A activity.

The results presented here suggest modest potential for clinical CYP3A4/5 inhibitors to inhibit non-CYP enzymes in vivo, most notably several UGT enzymes. Ketoconazole’s antifungal properties have been studied in various fields, including gynecology-endocrinology, gynecology, and endocrinology.

What does ketoconazole block synthesis of?

Abstract. Ketoconazole, a broad-spectrum, antifungal drug that is administered orally, has been shown to inhibit sterol synthesis in fungi. When gynecomastia developed in some patients taking this drug, we investigated the effects of ketoconazole on steroid synthesis in humans and in isolated adrenal cells from rats. In healthy humans, the cortisol response to adrenocorticotropic hormone was significantly blunted 4 hours after a 400-mg or 600-mg dose. The inhibition persisted for up to 8 hours and was absent by 16 hours. This finding indicated that adrenal androgen response was reduced. Easily achieved therapeutic concentrations of ketoconazole virtually eliminated corticosterone production by isolated adrenal cells from rats. Although ketoconazole at currently used doses has never been documented to cause clinical hypoadrenalism, caution is urged in high- or multiple-dose trials. The drug may prove useful as an agent to block steroid synthesis.

Ketoconazole inhibits cortisol secretion of an adrenal adenoma in vivo and in vitro.

Engelhardt D, Mann K, Hörmann R, Braun S, Karl HJ. Engelhardt D, et al. Klin Wochenschr. 1983 Apr 1;61:373-5. doi: 10. 1007/BF01485030. Klin Wochenschr. 1983. PMID: 6306332.

What does ketoconazole inhibit?

Ketoconazole, an antifungal agent, has been shown to inhibit testicular and adrenal steroid synthesis in high doses, making it a potential treatment for advanced prostate cancer. A study comparing twelve patients with metastatic prostate carcinoma on long-term high dose ketoconazole therapy with 12 control volunteers found that ketoconazole is a potent inhibitor of steroid synthesis. The study found that serum levels of testosterone, androstenedione, and dehydroepiandrosterone sulphate were lower in the ketoconazole group, while plasma progesterone, luteinizing hormone, and adrenocorticotropin were higher in the control group. The study also found that basal 17-hydroxyprogesterone and progesterone rose in the ketoconazole group after Cosyntropin stimulation, and progesterone rose in the ketoconazole group after human chorionic gonadotropin stimulation. The ability of ketoconazole to inhibit steroid synthesis suggests its potential in treating steroid-dependent diseases. Frequent high dose ketoconazole therapy can also inhibit adrenal steroid synthesis, which is important for patients undergoing stressful situations.

What CYP does ketoconazole inhibit?

CYP3A Ketoconazole is extensively used as an ‘index’ inhibitor of human cytochrome P450-3A (CYP3A) isoforms in the academic, regulatory, and drug development communities.’);))();(function()(window. jsl. dh(‘ctcrZ4bZF6C79u8P3pKdqAg__37′,’

What enzyme does ketoconazole block?

Ketoconazole has been found to interfere with steroidogenesis in patients and rat in vitro systems. This study aimed to elucidate the site of inhibition in the adrenal gland. Although ketoconazole impaired adrenocorticotropic hormone stimulated cyclic (c)AMP production, dibutyrl cAMP addition did not bypass the steroidogenic blockade, indicating that the critical ketoconazole-inhibited step was distal to cAMP.

Addition of radiolabeled substrates to isolated adrenal cells and analysis of products by high performance liquid chromatography demonstrated a ketoconazole block between deoxycorticosterone (DOC) and corticosterone. This 11-hydroxylase step is carried out by a P450-dependent mitochondrial enzyme. No restriction of progesterone or pregnenolone conversion to DOC was detected, steps carried out by non-P450-dependent microsomal enzymes. Inhibition of cholesterol conversion to pregnenolone by mitochondrial fractions indicated a second block at the side chain cleavage step, another mitochondrial P450-dependent enzyme. Adrenal malate dehydrogenase, a non-P450-dependent mitochondrial enzyme, was not inhibited while renal 24-hydroxylase, a P450-dependent mitochondrial enzyme in another organ, was blocked by ketoconazole.

The study concludes that ketoconazole may be a general inhibitor of mitochondrial P450 enzymes. This finding suggests that patients receiving ketoconazole be monitored for side effects relevant to P450 enzyme inhibition. Furthermore, the drug action may be beneficially exploited in situations where inhibition of steroidogenesis is a therapeutic goal.

References from previous studies on ketoconazole include Burton K’s study on the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid, Brass C., Galgiani J. N., Blaschke T. F., Defelice R., O’Reilly R. A., Stevens D. A. Disposition of ketoconazole, an oral antifungal, in humans, and others. The study also raises the possibility that this drug action may be beneficially exploited in situations where inhibition of steroidogenesis is a therapeutic goal.

Is ketoconazole a DHT blocker?

Local ketoconazole 2% can potentially inhibit DHT production and/or DHT binding to AR. Finasteride therapy adjunct with ketoconazole shampoo could potentially block the DHT pathway more completely; however, further clinical trials are warranted.

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What is the strongest natural DHT blocker?

Dr. Howell says that to reduce DHT levels naturally, you can consider dietary changes and supplements such as saw palmetto, green tea, pumpkin seeds, and foods rich in zinc. Regular exercise and maintaining a healthy diet can also help.

What are the most effective DHT Blockers available in the market?. Dr. Eric Howell, board-certified dermatologist, talks about DHT blockers, how they work and which ones are the most effective to stimulate hair growth.

Table of Content: What is a DHT blocker? | How do they work? | Do you need a prescription? | How to get a prescription? | About DHT | FAQ.

What inhibits DHT the most?

Green tea, onion, pumpkin seeds, and edamame are some foods that may help lower DHT levels and prevent hair loss.

Dihydrotestosterone (DHT) is a hormone similar to testosterone. It plays a role in the growth of facial, pubic, and body hair during puberty.

However, high levels of DHT may contribute to hair loss.

Your body naturally converts about 10% of testosterone into DHT using an enzyme called 5-alpha reductase.

Does ketoconazole suppress cortisol?

Learning points. Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome. Ketoconazole and osilodrostat appear to act in a synergistic manner.

Summary. Here, we describe a case of a patient presenting with adrenocorticotrophic hormone-independent Cushing’s syndrome in a context of primary bilateral macronodular adrenocortical hyperplasia. While initial levels of cortisol were not very high, we could not manage to control hypercortisolism with ketoconazole monotherapy, and could not increase the dose due to side effects. The same result was observed with another steroidogenesis inhibitor, osilodrostat. The patient was finally successfully treated with a well-tolerated synergitic combination of ketoconazole and osilodrostat. We believe this case provides timely and original insights to physicians, who should be aware that this strategy could be considered for any patients with uncontrolled hypercortisolism and delayed or unsuccessful surgery, especially in the context of the COVID-19 pandemic.

Ketoconazole–osilodrostat combination therapy appears to be a safe, efficient and well-tolerated strategy to supress cortisol levels in Cushing syndrome.

Ketoconazole and osilodrostat appear to act in a synergistic manner.

Does ketoconazole block DHT?

Testosterone, a very similar hormone, is converted to DHT with the help of an enzyme called 5-alpha reductase (5AR). It’s thought that ketoconazole blocks the action of 5AR in your body. By doing this, ketoconazole lowers DHT levels and may help slow hair loss. It may even support hair growth.

Does ketoconazole inhibit testosterone?

Ketoconazole causes a rapid and sustained decrease in serum testosterone. It also is as effective as castration in causing a decrease in the weight of the normal ventral prostate and inhibiting the growth of the Dunning R3327H prostatic aden- ocarcinoma.

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