The pharmacokinetic profile of UK-49,858 (fluconazole), a novel triazole antifungal agent which is being developed for oral and intravenous use, was determined in mice, rats, dogs, and humans. Comparative data following oral and intravenous administration showed that bioavailability was essentially complete in all four species. Peak concentrations in plasma of drug normalized to a 1-mg/kg dose level following oral administration, were relatively high: 0.7, 0.6, 1.1, and 1.4 ,ug/ml in mice, rats, dogs, and humans, respectively. UK-49,858 [2-(2,4,-difluorophenyl)-1,3-bis(lH-1,2,4-triazol-1-yl)propan-2-ol; fluconazole; Fig. 1] is a new systemically acting antifungal agent which has shown activity in several animal models of infection (14; P. F. Troke, R. J. Andrews, K. W. Brammer, M. S. Marriott, and K. Richardson, Antimicrob. Agents Chemother., submitted for publication). Typical oral 50% protective dose values against acute lethal systemic candidiasis in mice range between 0.1 and 0.3 mg/kg, demonstrating that the compound is between 20-and 100-fold more potent than ketoconazole in this model. Results of several studies with imidazole antifungal agents have shown that the pharmacokinetics of these compounds have a significant impact on their comparative efficacy in vivo. The pharmacokinetic profiles of such imidazole antifungal agents as miconazole (3, 12), econazole (13), and clotrimazole (7, 15) were characterized by poor oral bioavailability and low plasma concentrations due to significant first-pass metabolism and a large volume of distribution. The recent introduction of ketoconazole (1) has seen the advent of imidazole antifungal drugs with good systemic bioavailability and relatively high plasma concentrations. However, in common with previous imidazoles, ketoconazole is highly bound to plasma proteins (4, 11), is extensively metabolized (9), and exhibits dose-dependent kinetics in both animals (1) and humans (2, 5). This report describes the pharmacokinetic profile of the bistriazole UK-49,858, which is markedly different from that of ketoconazole and related imidazoles and assesses the potential contribution of this profile to the efficacy of the drug in vivo. MATERIALS AND METHODS
Tioconazole (UK-20,349), a new antifungal imidazole derivative, was compared with miconazole for activity in vitro against Candida spp., Torulopsis glabrata, Cryptococcus neoformans, Aspergillus spp., and dermatophyte fungi ( Trichophyton spp. and Microsporum spp.). Tioconazole was more active than miconazole against all the fungal species examined except Aspergillus , against which both agents showed similar activity. Both tioconazole and miconazole inhibited the growth of all fungi examined at concentrations well below their quoted minimum inhibitory concentrations. Their activity against fungi in vivo was investigated in mice infected systemically with Candida albicans . Both agents significantly reduced the numbers of viable Candida cells recoverable from the kidneys of infected animals, with tioconazole producing a generally more marked reduction. After administration of a single oral dose (25 mg/kg) to beagle dogs or white mice, higher and more sustained circulating levels of bioactive drug were detectable of tioconazole than of miconazole. These observations suggest that tioconazole may have potential in the treatment of both superficial and systemic mycoses in humans.
Fluconazole (UK-49,858), a novel bis-triazole antifungal agent, was given orally to groups of 10 male volunteers at doses of 25 and 50 mg/day for 28 days. Blood samples for testosterone estimation were taken from these and from a placebo group at several time points on days 1, 14, and 28 of the study, and the assay results demonstrated that the compound had no significant effect on circulating testosterone levels. Similarly, in studies with rat Leydig cells in vitro, fluconazole at concentrations up to 10 pg/ml was found to be only a weak inhibitor of testosterone production, whereas ketoconazole caused more than 50% inhibition at 0.1 ,ug/ml. It is concluded that fluconazole, in contrast to ketoconazole, has little effect on the biosynthesis of testosterone by mammalian cells.Imidazole antifungal drugs, including ketoconazole and miconazole, are recognized as inhibitors of certain cytochrome P-450-dependent enzymes which participate in the synthesis of steroid hormones in the gonads and the adrenals (7,10,14,15). With ketoconazole, this property has led to the occasional incidence of clinically overt hormonal deficiencies (2, 9); as such effects are undesirable in an antimicrobial agent, fluconazole (UK-49,858), a novel bis-triazole antifungal compound (4, 12) which is undergoing clinical evaluation, has been assessed for its ability to modulate plasma testosterone concentrations in adult male volunteers and to interfere with testosterone biosynthesis by rat Leydig cells in vitro. MATERIALS AND METHODSHuman volunteer study. Thirty healthy male volunteers, ages 18 to 45 years, were included in a double-blind study to investigate the effect of fluconazole on circulating testosterone levels. Groups of 10 subjects were given either placebo or fluconazole (25 or 50 mg) once daily for 28 days. Blood samples were taken from each subject before dosing and at nine time points after dosing on days 1, 14, and 28 of the study. Plasma testosterone was measured by radioimmunoassay (Travenol Laboratories Ltd., Egham, Surrey, England), and the concentration of fluconazole in each sample was estimated by a specific gas chromatographic method (16).Studies with isolated rat testis cells. The method used for investigating the effects of fluconazole and ketoconazole on basal and human chorionic gonadotropin (hCG)-stimulated testosterone production by rat Leydig cells in vitro was based on a published procedure (10). Male CD rats (350 g) (Charles River, Manston, Kent, England) were killed, and the testes were removed. Decapsulated testes were shaken for 20 min at 37°C with 200 U of collagenase (type 1A; Sigma Chemical Co., Poole, Dorset, England) per ml in incubation medium comprising medium 199 (Gibco Ltd., Paisley, Scotland) with 0.2% (wt/vol) bovine serum albumin (fraction V; Sigma). After the tubules and debris had settled for 10 min under gravity, the suspended cells were collected and washed twice with centrifugation (100 x g, 10 min) in incubation medium. Fluconazole and ketoconazole were dissolved in propane-1,2-diol and dilu...
Peptidoglycan transpeptidase activity has been studied in cells of Escherichia coli 146 and Pseudomonas aeruginosa 56 made permeable to exogenous, nucleotide-sugar peptidoglycan precursors by ether treatment. Transpeptidase activity was inhibited, in both organisms, by a range of penicillins and cephalosporins, the Pseudomonas enzyme being more sensitive to inhibition in each case. Conversely, growth of E. coli 146 was more susceptible to these antibiotics than growth of P. aeruginosa 56. Furthermore, similar transpeptidase inhibition values were obobtained for the four penicillins examined against the Pseudomonas enzyme, although only two of these (carbenicillin and pirbenicillin) inhibited the growth of this organism. We therefore conclude that the high resistance of P. aeruginosa The target site of penicillins is thought to be the enzyme peptidoglycan transpeptidase (18), which catalyzes the final reaction in bacterial cell wall biosynthesis, i.e., the formation of an interpeptide linkage between the amino acid side chains of the peptidoglycan polymer (1). This enzymatic reaction has been shown to occur in both gram-positive and gram-negative bacteria (2,5,9,10,21), and is thought to be common to most, if not all, bacteria. Pseudomonas aeruginosa however, is characteristically resistant to the majority of /-lactam antibiotics (15 Preparation of UDP-MurNAc-pentapeptide.
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