No _in vitro_ or _in vivo_ studies of levoketoconazole metabolism have been performed. [Ketoconazole] is known to be hepatically metabolized to several inactive metabolites, mainly through oxidation of the imidazole and piperazine rings, together with oxidative O-dealkylation and aromatic hydroxylation. Levoketoconazole is known to both induce and strongly inhibit CYP3A4.
Ketoconazole is partially metabolized, in the liver, to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.
IDENTIFICATION AND USE: Ketokonazole is used as antifungal medication. HUMAN EXPOSURE AND TOXICITY: Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole therapy. Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation. Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury. Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and rarely death has occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy, but occasionally may be apparent within the first week of therapy. Some patients with ketoconazole-induced hepatotoxicity had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving high oral ketoconazole dosage for short treatment durations and in patients receiving low oral dosage of the drug for long durations. Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium (onychomycosi or the treatment of chronic, refractory dermatophytoses. Ketoconazole-induced hepatitis has been reported in some children. Usual dosages (ie, 200-400 mg daily) of ketoconazole have been reported to transiently (for 2-12 hours) inhibit testicular testosterone synthesis. A compensatory increase in serum luteinizing hormone (LH) concentrations may occur. Dosages of 800-1200 mg daily have been reported to have a more prolonged effect on testosterone synthesis; in one study in males receiving these high dosages, serum testosterone concentrations remained at a subnormal level (ie, less than 300 ng/dL) throughout the day in about 30% of those receiving 800 mg daily and in all of those receiving 1200 mg daily. Oligospermia, decreased libido, and impotence often occurred in these males and azoospermia occurred rarely. The drug apparently directly inhibits synthesis of adrenal steroids and testosterone in vitro and in vivo. Ketoconazole appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (eg, 11beta-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme). Overall the results show that many of the commonly used azole fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine-disrupting effects in humans. ANIMAL STUDIES: After oral administration toxicity was manifested in mice, rats and guinea pigs by sedation, catalepsy, ataxia, tremors, convulsions and pre-lethal loss of the righting reflex at doses >320 mg/kg. In dogs, toxicity was manifested by diarrhea and vomiting at doses >80 mg/kg. Ketoconazole has been administered by the oral (gavage) and intravenous routes to mice, rats, guinea pigs and dogs. Toxicity after intravenous administration was manifested by spasms, convulsions and dyspnea in rats, mice and guinea pigs; pre-lethal loss of the righting reflex occurred in mice and guinea pigs, and dogs. Toxicity in dogs was also manifested by licking and convulsions. In rats the overall incidence of and type of tumors was not significantly different between treated and control groups, except for high-dosed female rats who had a decrease of the overall tumor rate. In developmental studies in rats the incidence of stillborn fetuses increased from a control value of 0.5% to 32.7% in rats dosed with 40 mg/kg and cannibalization of young occurred in two litters. In mice a significant decline in sperm motility and density in cauda epididymis was noted. A sharp decline in fertility (50% negative) in ketoconazole treated mice was observed. A significant reduction in the total protein and sialic acid contents of testes, epididymis, seminal vesicle and ventral prostate were noticed. The cholesterol contents of testes were raised while fructose contents of seminal vesicle were reduced significantly. The ketoconazole treatment altered the biochemical milieu of the reproductive tract. In the rabbit, ketoconazole produces evidence of maternal toxicity, embryotoxicity and teratogenicity at a high dose of 40 mg/kg/day. Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. ECOTOXICITY STUDIES: Ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.
Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole. These abnormalities are usually transient and asymptomatic and uncommonly require dose adjustment or discontinuation. Clinically apparent hepatotoxicity from ketaconazole is well described in the literature and is estimated to occur in 1:2,000 to 1:15,000 users. The liver injury typically presents with an acute hepatitis-like picture 1 to 6 months after starting therapy. While most cases present with a hepatocellular pattern of injury, cholestatic forms have been described. Rash, fever and eosinophilia are rare as is autoantibody formation. Recovery upon stopping therapy may be delayed and generally takes 1 to 3 months. Severe cases with acute liver failure and death or need for emergency liver transplantation have been described.
◉ Summary of Use during Lactation:Because there is little published experience with ketoconazole or levoketoconazole during breastfeeding and its potential liver enzyme inhibition and liver toxicity, other agents are preferred. The manufacturers recommend that mothers taking ketoconazole or levoketoconazole avoid breastfeeding during treatment and for 1 day after the last dose.
Use of ketoconazole shampoo or topical use on the skin by the mother poses little to no risk to the breastfed infant. However, topical use on the breast or nipples should be avoided in nursing mothers because of possible oral ingestion by the infant and the availability of safer alternatives. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.
◉ Effects in Breastfed Infants:A mother taking ketoconazole 200 mg orally for 10 days noticed no adverse effects in her breastfed 1-month-old infant.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
来源:Drugs and Lactation Database (LactMed)
毒理性
暴露途径
这种物质可以通过摄入被身体吸收。
The substance can be absorbed into the body by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
毒理性
吸入症状
咳嗽。
Cough.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
Levoketoconazole has a Tmax of ~1.5-2 hours regardless of dose, while the Cmax increases proportionally with the dose. The AUC increases greater than dose proportionally over the recommended range of 150-600 mg. Co-administration of a single 600 mg oral dose with a high-fat meal increased the AUC by 30% with no change in Cmax and a delay in the median Tmax from two to four hours. The pharmacokinetics of racemic [ketoconazole] are not significantly different in patients with renal impairment; given the extensive hepatic metabolism of [ketoconazole], it is expected that hepatic impairment will affect the pharmacokinetics of levoketoconazole.
Approximately 13% of racemic [ketoconazole] is excreted in the urine, 2-4% as unchanged drug, while the major excretion route is in the feces, accounting for ~57%.
Ketoconazole is rapidly absorbed from the GI tract. Following oral administration, ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.
The effect of food on the rate and extent of GI absorption of ketoconazole has not been clearly determined. Some clinicians have reported that administration of ketoconazole to fasting individuals results in higher plasma concentrations of the drug than does administration with food. However, the manufacturer states that administration of ketoconazole with food increases the extent of absorption and results in more consistent plasma concentrations of the drug. The manufacturer suggests that food increases absorption of ketoconazole by increasing the rate and/or extent of dissolution of ketoconazole (e.g., by increasing bile secretions) or by delaying stomach emptying.
