Itraconazole is metabolized predominantly by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing.
Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.
Transient, mild-to-moderate elevations in serum aminotransferase levels occur in 1% to 5% of patients on itraconazole. These elevations are largely asymptomatic and self-limited, resolving even with continuation of therapy. Clinically apparent hepatotoxicity is rare but has been well described and can be severe and even fatal. The liver injury from itraconazole typically presents 1 to 6 months after starting therapy with symptoms of fatigue and jaundice. The pattern of serum enzyme elevations is typically cholestatic (Case 1), but cases of severe hepatitis with acute liver failure typically have a hepatocellular enzyme pattern (Case 2). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Recovery upon stopping therapy can be delayed for several weeks and generally takes 4 to 10 weeks, although in some cases recovery may be prolonged.
◉ Summary of Use during Lactation:No information is available on the clinical use of itraconazole during breastfeeding. However, limited data indicate that maternal itraconazole produces levels in milk that are less than the 5 mg/kg daily doses that have been recommended to treat infants. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If itraconazole is used during breastfeeding, monitoring of the infant’s liver enzymes should be considered, especially with long courses of therapy.
◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.
The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.
Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole.
Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin.
The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%.
The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100 mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table /provided/.
Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200 mg itraconazole capsules b.i.d. (with a full meal) for 15 days [Table#7580]
Thirty healthy men received single 200 mg doses of itraconazole capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When itraconazole capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when itraconazole capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% +/- 37% and 42% +/- 39%, respectively. When itraconazole capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone.
[EN] COMPOSITIONS AND METHODS FOR THE TREATMENT OF FUNGAL INFECTIONS<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE TRAITEMENT D'INFECTIONS FONGIQUES
申请人：CELLIX BIO PRIVATE LTD
公开号：WO2018096497A1
公开（公告）日：2018-05-31
The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX or Formula X and, the methods for the treatment of fungal infections may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of fungal infections.
New triazole antifungal agents having C6S7 or S6C7 bridges are disclosed. These triazoles provide alternatives to existing antifungals in terms of formulation, bioavailability and activity.
FLUORESCENT ENDOPLASMIC RETICULUM TRACKERS FOR LIVE CELL IMAGING OF PATHOGENIC YEAST
申请人：Ramot at Tel Aviv University Ltd.
公开号：US20200072711A1
公开（公告）日：2020-03-05
Particular 1,2,3-triazole- and 1,2,4-triazole-based compounds can be used as fluorescent probes. The compounds can optionally be substituted with one or two fluorine atoms. The compounds are effective as specific endoplasmatic reticulum (ER)-trackers for live cell imaging in a fungal cell, such as a pathogenic yeast. Compositions including the fluorescent probes can be used in methods for tracking the endoplasmic reticulum in a fungal cell.
Stereoselective determination of the epimer mixtures of itraconazole in human blood plasma using HPLC and fluorescence detection
作者：Christina Pyrgaki、Steve J. Bannister、Lajos Gera、John G. Gerber、Joseph Gal
DOI：10.1002/chir.20932
日期：2011.8
for the determination of the drug in biological fluids are needed for the elucidation of that role. We report a stereoselectiveHPLC method that incorporates solvent extraction, the use of an internal standard, two chiral stationary phases in series, and fluorescencedetection. The procedure is enantioselective and partially diastereoselective and provides the concentrations in bloodplasma of the two
[EN] A PROCESS FOR THE PREPARATION OF ITRACONAZOLE<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ITRACONAZOLE
申请人：NEULAND LAB LTD
公开号：WO2011121594A1
公开（公告）日：2011-10-06
The present invention encompasses a process for the preparation and purification of cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methxoy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one of formula (I) to obtain a specifically desired four possible sterioisomer.
