Systemic antifungal potential, safety, biotransport and transformation of micronazole nitrate

Brugmans, J; Cutsem, J. Van; Heykants, J.; Schuermans, V.; Thienpont, D

doi:10.1007/bf00561752

Cited by 76 publications

(19 citation statements)

References 9 publications

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“…Renal clearance is the major route of excretion of UK-49,858, with metabolism accounting for less than 10% of total drug excreted in mice and dogs. This pattern of excretion reflects the relative polarity and metabolic stability of the drug, unlike other imidazole antifungal drugs, including miconazole and ketoconazole, all of which are extensively metabolized in animals and humans (3,4,11,13,16).…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans

Humphrey¹,

Jevons²,

Tarbit³

1985

Antimicrob Agents Chemother

350

180

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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

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetic evaluation of UK-49,858, a metabolically stable triazole antifungal drug, in animals and humans

Humphrey¹,

Jevons²,

Tarbit³

1985

Antimicrob Agents Chemother

350

180

View full text Add to dashboard Cite

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“…Orally administered clotrimazole is frequently associated with gastrointestinal intolerance (13,14,24) and, since parenteral formulations are not available, its value in systemic therapy is severely limited. Miconazole appears to be better tolerated (3,13) and is showing some promise in the therapy of systemic mycoses when administered either orally or parenterally (6,11,13,16,20,21).…”

mentioning

confidence: 99%

Antifungal Activity of Tioconazole (UK-20,349), a New Imidazole Derivative

Jevons

Gymer

Brammer

et al. 1979

Antimicrob Agents Chemother

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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.

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“…1) (Daktarin®, Gyno-Daktarin®; R 14889, Janssen Pharmaceutica, Beerse), a synthetic 1-phenethyl-imidazole deri vative [10], is a potent broad-spectrum antifungal agent with strong bac tericidal effects on gram-positive bacteria [25]. In experimental dermatophytic and candidal infections in guinea pigs, the substance proved to be very effective when administered orally as well as topically [25], Double blind and controlled studies in man showed its potent activity in dermato mycoses [2,3,5,8,12,16,23,26], onychomycoses [2,14,16], vulvovaginal mycoses [I, 4, 9, 11, 13, 15, 17-20, 22, 24], gastrointestinal candidiasis [6], and deep mycoses [7,21]. This paper reports on the clinical and microbiological efficacy of micon azole in the treatment of dermatomycoses, and on the sensitivity to the drug of all pathogenic fungus strains isolated before, during, and after the study.…”

Section: Introductionmentioning

confidence: 99%