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To investigate the localisation of fipronil in dog skin, [14C]-fipronil was topically applied to a male beagle dog (spot-on administration) at the therapeutic dose of 10 mg/kg. By means of autohistoradiography, the radioactivity was precisely detected in the skin and appendages at various intervals after application. Radioactivity was predominantly observed within the stratum corneum, the viable epidermis, and in the pilo-sebaceous units (mainly in the sebaceous glands and epithelial layers). [14C]-fipronil was significantly detected in these structures up to 56 days post-treatment, in the application zone (neck) but also in the lumbar zone, thus indicating the mechanical displacement of fipronil. No radioactivity was detected in either the dermal or the hypodermal layers, confirming the low percutaneous passage of fipronil.

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Absorption and elimination of fluconazole after oral administration of a 100-mg capsule were unaffected by concomitant administration of an antacid containing aluminum and magnesium hydroxides.Fluconazole is a new bis-triazole which has shown good antifungal activity in animal models of fungal infection (4) and in clinical studies of vaginal candidiasis (1, 9), oropharyngeal candidiasis in patients with acquired immunodeficiency syndrome and malignancies (3), and dermatophyte infections (10).As well as having good absorption after oral administration (>95% bioavailability), fluconazole has a long half-life (25 to 30 h) in plasma and exhibits low protein binding (12%). Fluconazole is excreted mainly unchanged in the urine (2).Optimal absorption of ketoconazole after oral administration has been shown to require normal gastric acidity. It has been postulated that the low aqueous solubility of ketoconazole in mildly acidic or neutral conditions is the reason for this impaired absorption in patients with hypochlorhydria, and this was later verified with volunteers (12). Fluconazole, a less lipophilic, more weakly basic bis-triazole derivative, is water soluble in both neutral and acidic conditions and may not, therefore, be subject to the same limitations in gastrointestinal absorption. However, a significant proportion of patients who suffer from fungal infections do have impaired gastric acidity, whether it be from gastric secretory failure in patients with acquired immunodeficiency syndrome (6) postadministration. Blood samples (8 ml) were withdrawn immediately before and 1, 2,4,6,8,12, 24, 36, 48, 72, 96, 120, and 144 h after administration of each fluconazole dose. Plasma from each sample was separated, frozen at -20°C, and stored until assay at Biosciences by a gas chromatographic method for which the limit of detection was 0.1 ,ug/ml (13). Standard calibration curves established with samples with concentrations of 0.1 to 5 jig/ml during the study to control the linearity and accuracy of the method had relative standard deviations which varied from 2.4 to 5.4%. Replicate assays (n = 6) on samples with concentrations of 0.25 and 4 ,ug/ml had relative standard deviations of 5.9 and 2.6%, respectively.

1. After oral administration of 14C-thymoxamine to rat and man the total 14C excreted in urine and faeces was determined. 2. Six metabolites were isolated from the excret of man and rat by chemical extraction and identified by g.l.c.-mass spectral analyses. 3. Two other metabolites, highly polar and resistant to enzymic hydrolysis, were isolated by extraction on XAD2 resin and h.p.l.c. analysis. These two metabolites were identified by n.m.r. and by mass spectrometry in the fast atomic bombardment mode. 4. These two major metabolites of thymoxamine in man and rat have been identified and characterized as the sulphate conjugates of desacetyl-thymoxamine and N-monodesmethyl-desacetyl-thymoxamine.