The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59%o that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.

tion of amido and hydroxyl groups in model compounds so that the positions of these groups in the ground state 5 more closely resemble their positions in the transition state for lactonization.Perhaps the hydroxyamide 5 will be more susceptible than la to imidazole-catalyzed lactonization. The parent acid of 5 has been reported to lactonize ~3 X 101 234 times faster than hydroxymethylbenzoic acid.19 (19) D. R. Storm and D. E. Koshland, Jr., Proc. Nat. Acad. Set.

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SummaryAntiherpetic activity of AME was demonstrated in in vitro inactivation tests and in cell culture systems against herpes zoster and five strains of herpes simplex virus.The recently reported activity of water-soluble amphotericin B methyl ester (AME) against lipid-bound viruses (2, 3) suggested the potential use of this polyene antibiotic for topical treatment of herpetic infections. Extensive studies in our laboratories have shown significant antiherpetic activity with AME, as evidenced by the inactivation in vitro and by the inhibition in cell cultures of herpes zostervaricella and five strains of herpes simplex virus. Activity was independent of type or strain relationships among the viruses tested. Since host-cell membrane components of the lipid viral envelope have been proposed as the site of interaction with AME (3), it was essential for these comparative studies to prepare all strains of herpesviruses in the same host-cell line, the host of choice being MA-184 human newborn foreskin cells. The minimum effective concentration of AME necessary for maximum virueidal activity was limited by and directly related to the size of the virus population. While quantitative sensitivities were similar in most cases, a comparative analysis using two strains of herpes simplex virus showed different kinetics of inactivation for each strain. The present report deals ~dth these findings.Amphoteriein B methyl ester (AME) is a semisynthetie antifungal agent produced by esterification with diazomethane of the heptaene macrolide antibiotic, amphotericin B (5). Chemically, AME is a base which easily forms watersoluble salts with mineral and organic acids. In contrast, the parent compound Arch. ¥iroL 48/4 27

The comparative efficacy of amphotericin B and amphotericin B methyl ester (AME) against experimental histoplasmosis, blastomycosis, cryptococcosis, and candidosis in mice was assessed by determining the effect of daily intraperitoneal therapy on 21-day survival and persistence of organisms in internal organs. AME, like amphotericin B, was effective against each of the experimental infections, but the efficacy was lower than the parent compound. For Histoplasma and Blastomyces infections the mean effective dose (ED50) of amphotericin B was 0.3 mg/kg, whereas the corresponding values for AME, respectively, were 2.4 and 2.8 mg/kg. For Cryptococcus infection the ED50 for amphotericin B was 0.2 mg/kg compared with 2.0 mg/kg for AME. The ED.0 of amphotericin B for Candida infection was lower than 0.05 mg/kg and the value of AME was between 0.5 to 0.05 mg/kg. The colony counts from internal organs of the surviving animals after the therapeutic regimens were compatible with the data on survival.

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High performance liquid chromatographic (HPLC) procedures were utilized for the rapid and efficient separation and characterization of the aromatic heptaene macrolide group of antifungal antibiotics. The instrument utilized a 350 nm phosphor converted ultraviolet detector and a It Bondapak C18 column packing. Optimum resolution of eleven commercial aromatic heptaene macrolide preparations was obtained with solvent systems consisting of mixtures of acetonitrile and 0.05 M aqueous sodium citrate buffer, pH 5.3. The presence of two distinct types of aromatic heptaene macrolides with numerous well-defined individual components has been established.The polyene macrolide antifungal antibiotics1,2) are among the most abundant of microbial antibiotic products. Classified as tetraenes, pentaenes, hexaenes, and heptaenes according to the number of conjugated double bonds in the molecule, these antibiotics are generally recognized for their complexity and difficulty of characterization.In the past a number of different analytical procedures including paper chromatography, thin-layer chromatography and countercurrent distribution has been used for the separation and characterization of these complex antibiotics with varied but generally limited success. The separation of the aromatic subgroup of heptaene macrolides, in particular, by these techniques was most inadequate. Countercurrent distribution procedures at best permitted the gross separation of these antibiotics with several serious drawbacks including excessive time for resolution and product instability.The technique of high performance liquid chromatography (HPLC) was first reported for the analysis of different polyene macrolide antibiotics in 19731) and later more fully described in 19744). The HPLC results with the non-aromatic heptaene macrolides such as amphotericin B and candidin clearly exceeded those obtained previously by other analytical procedures including countercurrent distribution.Preliminary HPLC studies5) with three closely related aromatic heptaene macrolides also indicated the potential of this analytical procedure in the characterization and differentiation of these numerous complex antibiotics.The recent availability of more efficient HPLC column packing materials enabled further improvement in the resolution and characterization of all polyene macrolide antibiotics. The results of HPLC studies with eleven better known members of the aromatic heptaene group are reported here. Materials and MethodsHigh performance liquid chromatograph A noncommercial HPLC instrument previously described4) was employed throughout these studies.

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