Quote from Dr. Garrett Smith on February 20, 2019, 5:16 pm

Any medication that inhibits certain liver detoxification pathways (cytochrome P450 systems) that are involved in the breakdown of Poison/"Vitamin A" will eventually cause Poison/"Vitamin A" toxicity if they are taken long enough.  It may simply be the start of a person's road to toxicity, or it may be one more factor in how they get/got there. In fact, it is entirely possible that their main mechanism of action is increasing Poison/"Vitamin A" in the system that kills the pathogen...the hope is that it doesn't kill the patient first.  It's a lot like the old treatments of syphilis with mercury..."great" if it kills the pathogen before the host, not so great if the opposite happens.  We now we look at that idea in horror...and my goal is to help the world eventually look at Poison/"Vitamin A" in the exact same way.

Ketoconazole inhibits the in vitro and in vivo metabolism of all-trans-retinoic acid.

Ketoconazole, an antifungal agent and inhibitor of certain mammalian cytochrome P-450-dependent enzymes, was studied for its effects on the in vitro and in vivo metabolism of all-trans-retinoic acid (RA). In vitro, ketoconazole (Ki = 0.75 microM) inhibited, in an apparently competitive manner, the cytochrome P-450-mediated metabolism to 4-hydroxy- and 4-keto-retinoic acids by hamster liver microsomes. In vivo, ketoconazole suppressed the formation of polar RA metabolites by normal rats dosed intrajugularly with 200 ng of [3H]RA. After p.o. treatment with ketoconazole (2.5-40 mg/kg) given 1 hr before the [3H]RA injection, the radioactivity extracted from the liver consisted of 25 to 50% polar metabolites (control 66 +/- 1%) and 50 to 75% undegraded RA (control 34 +/- 1%) as evidenced by reverse-phase high-performance liquid chromatography. Time course experiments showed that ketoconazole's inhibitory effects lasted for 3 hr. Our data indicate the quantitative importance of the cytochrome P-450 enzymatic pathway in the biotransformation of RA. They also suggest that ketoconazole is capable of prolonging the biological half-life of RA and of improving the tissue levels of this compound.

Translation for what is above and what is following:  The -azole antifungal medications slow down the liver's ability to break down Poison/"Vitamin A", thus leading to long-term toxicity.

Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.

Fluconazole inhibited the NADPH-dependent cytochrome P450-mediated catabolism of trans-retinoic acid in a concentration-dependent manner.

Voriconazole-induced Phototoxicity in Children

In one study, 3 patients with cutaneous side effects were found to have all-trans retinol values at the top end of normal range  during voriconazole therapy.¹¹ They hypothesized that one step in the metabolic breakdown of all-trans retinol or 13-cis retinol is inhibited by voriconazole.

Muco-cutaneous retinoid-effects and facial erythema related to the novel triazole antifungal agent voriconazole.

Voriconazole is a new azole antifungal drug with activity against a wide range of systemic fungal pathogens, including Aspergillus spp. Five patients with chronic invasive aspergillosis were treated for 12-58 weeks with voriconazole, 200 mg twice daily and developed facial erythema and cheilitis. One who received 58 weeks of therapy also developed discoid lupus erythematosus-like lesions on both sides of her neck. Both erythema and cheilitis resolved after discontinuation of voriconazole. Serum retinoids were elevated in the three patients in whom they were measured. Voriconazole has the potential for retinoid-like side-effects and facial erythema.

Voriconazole-Induced Photosensitivity

The etiology of voriconazole-induced photosensitivity remains unclear, but may be due to indirect retinoid effects or direct phototoxic effects of voriconazole or one of its metabolites.^5,9–11 Photosensitivity reactions appear to be idiosyncratic, rather than dose-dependent.² Counseling and recommendations regarding avoidance of sun exposure and use of sunscreens may lessen or resolve a majority of cases of voriconazole-induced photosensitivity despite drug continuation.

Voriconazole-induced retinoid-like photosensitivity in children.

Voriconazole is a new triazole antifungal agent with activity against a wide range of systemic fungal pathogens, including Aspergillus spp. Photosensitivity is a rarely reported side effect of voriconazole, hypothesized to be a result of retinoid-like effects. We report two children with chronic granulomatous disease to whom voriconazole was administered for chronic invasive aspergillosis. Severe photosensitivity occurred in both patients, one of whom had striking photodamage at the 5-month follow-up.

Sensitivity to light, whether skin-related, or eye-related, is classic Poison/"Vitamin A" toxicity.  This makes one wonder why Vitamin A is being added to sunscreens, doesn't it?

Successful Treatment of Coccidioidal Meningitis with Voriconazole

Because plasma retinoid levels have been reported to be high in patients with voriconazole photosensitivity [3], our patient was tested twice while receiving 400 mg of voriconazole twice daily. His retinol levels were 1300 μg/L on day 260 and 1747 μg/L on day 291. These values exceed the upper limit of normal for our laboratory (1100 μg/mL). The patient was not taking multivitamins or alternative medicines that might have provided a dietary source of retinoids.

He got hypervitaminosis A from the medication, and was NOT on any vitamins or other source of supplemental or pharmaceutical sources of Vitamin A.  If we stop the breakdown of Poison/"Vitamin A", we quickly develop toxicity.