terbinafine, Lamisil
Tissue distribution of terbinafine in rats.

Hosseini-Yeganeh M, McLachlan AJ.

Faculty of Pharmacy, College of Health Sciences, University of Sydney, Sydney, NSW, 2006, Australia.

Terbinafine is an allylamine antifungal agent that is highly lipophilic and keratophilic. The aim of this study was to investigate terbinafine distribution in peripheral and visceral tissues after intravenous administration to rats. Terbinafine, 6 mg/kg, was administered to 33 male Sprague-Dawley rats via a jugular vein cannula over 30 s. Groups of 3 rats were sacrificed at each of 11 time points (up to 24 h), and plasma and tissues were dissected, sampled, and analyzed by high-performance liquid chromatography. Terbinafine plasma concentrations declined in a triexponential fashion, with an estimated elimination half-life of 10 h. The estimated clearance of terbinafine in rats was 2 L/h/kg and the volume of distribution at steady state was 6 L/kg. The tissue-to-plasma partition coefficient (K(p)) of terbinafine for different tissues was calculated using the ratio of the area under the curve of concentration-time for tissues (AUC(tissue)) to that for plasma (AUC(plasma)), by parametric and semiparametric approaches. There was good agreement between K(p) estimates determined by different approaches. The preferential distribution of terbinafine to adipose and skin (K(p) = 49 and 45, respectively) was consistent with the lipophilicity of the drug. Uptake of terbinafine into brain (K(p) = 1.3) and muscle (K(p) = 1.0) was significantly lower. In conclusion, terbinafine displays extensive uptake to peripheral tissues, which contributes to the long elimination half-life of this drug. Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association

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terbinafine, Lamisil
Evaluation of terbinafine treatment in Leishmania chagasi-infected hamsters (Mesocricetus auratus).

Simoes-Mattos L, Teixeira MJ, Costa DC, Prata JR Jr, Bevilaqua CM, Sidrim JJ, Rocha MF.

Faculdade de Veterinaria (FAVET), Universidade Estadual do Ceara (UECE), Av. Paranjana 1700, Campus do Itaperi, Fortaleza, Ceara, Brazil. 1smattos yahoo.com

The objective of the present study was to assess the effect of terbinafine treatment in hamsters infected with Leishmania chagasi. Four of five groups of hamsters were infected with 3 x 10(7) L. chagasi promastigotes by the intracardiac route and submitted to different treatments of 30 days duration starting on the 30th day after inoculation. Group 1 was treated with 100mg/kg terbinafine PO, group 2 was treated with 80 mg/kg Glucantime IM, and group 3 was treated with a combination of the same dose of each drug by the same routes. Group 4 (control) received vehicle (Tween 80 [0.1%]+CMC[0.5%]+H(2)O [0.5 ml], PO). Spleen parasite burden and spleen relative weight were determined 3 days after the end of the treatment. The results were analyzed by the Kruskal-Wallis test (P < 0.05). There was no difference between the infected untreated and terbinafine-treated groups in spleen parasite burden (15.81+/-15.81 vs. 13.00+/-12.94, respectively). Terbinafine plus Glucantime (6.11+/-5.90) and Glucantime alone (4.83+/-4.82) significantly reduced spleen parasite burden compared to the infected untreated group (15.81+/-15.81, P<0.01). There was a difference in the relative weight of the spleen between the naive and the infected untreated groups (2.5+/-0.2 vs. 9.8+/-1.0, respectively) as well as between the naive and terbinafine groups (2.5+/-0.2 vs. 10.0+/-1.4, respectively). Glucantime alone and Glucantime plus terbinafine (2.5+/-0.2 and 4.2+/-0.6) significantly reduced the weight of the spleen in comparison with the infected untreated group. Even so, the spleen parasite burden was directly related to spleen weight. Terbinafine alone at the dose and schedule used had no effect on spleen parasite burden or relative spleen weight of L. chagasi-infected hamsters.

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terbinafine, Lamisil
Use of terbinafine in mouse and rat models of Pneumocystis carinii pneumonia.

Walzer PD, Ashbaugh A.

Research Service, Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA. peter.walzer med.va.gov

Terbinafine, an allylamine used to treat onychomycosis, has been reported to be active against rat Pneumocystis carinii in vitro and in vivo. By contrast, our in vitro data showed that the 50% inhibitory concentration of terbinafine against rat P. carinii is 3.7 microg/ml, a level that cannot be clinically achieved in serum. In the present study, terbinafine administered orally at doses of 20 to 400 mg/kg/day and 50 to 250 mg/kg/day was ineffective therapy for mouse and rat models of pneumocystosis, respectively. These results emphasize the complexities of P. carinii drug testing and the need for caution before considering studies in humans.

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terbinafine, Lamisil
Effects of a squalene epoxidase inhibitor, terbinafine, on ether lipid biosyntheses in a thermoacidophilic archaeon, Thermoplasma acidophilum.

Kon T, Nemoto N, Oshima T, Yamagishi A.

Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Komaba, Tokyo 153-8902.

The archaeal plasma membrane consists mainly of diether lipids and tetraether lipids instead of the usual ester lipids found in other organisms. Although a molecule of tetraether lipid is thought to be synthesized from two molecules of diether lipids, there is no direct information about the biosynthetic pathway(s) or intermediates of tetraether lipid biosynthesis. In this study, we examined the effects of the fungal squalene epoxidase inhibitor terbinafine on the growth and ether lipid biosyntheses in the thermoacidophilic archaeon Thermoplasma acidophilum. Terbinafine was found to inhibit the growth of T. acidophilum in a concentration-dependent manner. When growing T. acidophilum cells were pulse-labeled with [2-(14)C]mevalonic acid in the presence of terbinafine, incorporation of radioactivity into the tetraether lipid fraction was strongly suppressed, while accumulation of radioactivity was noted at the position corresponding to diether lipids, depending on the concentration of terbinafine. After the cells were washed with fresh medium and incubated further without the radiolabeled substrate and the inhibitor, the accumulated radioactivity in the diether lipid fraction decreased quickly while that in the tetraether lipids increased simultaneously, without significant changes in the total radioactivity of ether lipids. These results strongly suggest that terbinafine inhibits the biosynthesis of tetraether lipids from a diether-type precursor lipid(s). The terbinafine treatment will be a tool for dissecting tetraether lipid biosynthesis in T. acidophilum.

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terbinafine, Lamisil
In-vitro distribution of terbinafine in rat and human blood.

Yeganeh MH, McLachlan AJ.

Faculty of Pharmacy, University of Sydney, NSW, Australia.

The association of drugs with plasma lipoproteins has the potential to influence drug action and disposition. In this study, the uptake and distribution of the lipophilic antifungal drug, terbinafine, was investigated in rat and human blood and plasma. Fresh plasma was incubated with terbinafine (200-1000 ng mL(-1)), then subjected to vertical spin density gradient ultracentrifugation to separate protein fractions. The concentrations of terbinafine in each fraction was determined using a validated reversed-phase HPLC method. The association of terbinafine with very-low-density lipoproteins (15.5 +/- 7.1% of total concentration) in human plasma was significantly lower than that associated with fractions containing soluble proteins (28.0 +/- 6.2%), high- (26.8 +/- 7.7%) and low-density lipoproteins (31.6 +/- 4.6%). In rats terbinafine was found to be distributed evenly through plasma protein fractions. The association of terbinafine in lipoproteins was independent of concentration (over the range 200-1,000 ng mL(-1)) and species. The distribution of terbinafine was examined in human and rat blood and the blood-to-plasma ratio of terbinafine was 0.70+0.09 and 1.01 +/- 0.20, respectively, indicating higher association of terbinafine with plasma components than erythrocytes in humans. This study suggests that in humans and rats, terbinafine associates with a number of plasma proteins independently of terbinafine concentration. Alteration in plasma lipoprotein concentrations are therefore likely to influence terbinafine binding in blood and distribution in the body.

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terbinafine, Lamisil
Determination of terbinafine in tissues.

Yeganeh MH, McLachlan AJ.

Department of Pharmacy, University of Sydney, Sydney, NSW 2006, Australia.

Terbinafine and N-demethyl terbinafine concentrations were determined simultaneously in rat tissues by a high-performance liquid chromatography method. This method involved the homogenization of tissues (except for skin) followed by a liquid-liquid extraction. Skin samples were dissolved in sodium hydroxide prior to extraction. Terbinafine and its N-demethylated metabolite were assayed using a C(18) reversed-phase column with a mobile phase of acetonitrile and water (40:60) containing ortho phosphoric acid (0.02 M) and triethylamine (0.01 M), and UV detection (at 224 nm). The standard curve for the assay (constructed using clotrimazole as internal standard) was linear over the concentration range 100-3000 ng/g in skin and 10-600 ng/g in all other tissues. The inter- and intra-day precision for both terbinafine and metabolite was between 0.2% and 16%. The limit of quantification was 10 ng/g in all tissues and 100 ng/g in skin. This assay was found to be reliable and reproducible for the determination of terbinafine and N-demethyl terbinafine concentration in all rat tissues and has been used for tissue distribution studies. Copyright 2000 John Wiley & Sons, Ltd.

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terbinafine, Lamisil
Simultaneous determination of terbinafine HCL and triamcinolone acetonide by UV derivative spectrophotometry and spectrodensitometry.

El-Saharty YS, Hassan NY, Metwally FH.

Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr, El-Aini St., ET-11562, Cairo, Egypt. ysaharty hotmail.com

A binary mixture of terbinafine hydrochloride and triamcinolone acetonide was determined by three different methods. The first one concerned with determination of both drugs using first derivative (D(1)) spectrophotometric technique at 297 and 274 nm over concentration ranges of 5-30 and 4-24 microg ml(-1), with mean percentage accuracies 99.90+/-0.67 and 100.25+/-0.49, respectively. The second method depends on ratio-spectra 1st derivative (RSD(1)) spectrophotometry at 298 and 248 nm over the same concentration ranges with mean percentage accuracies 100.22+/-0.51 and 99.93+/-0.56, respectively. The spectrodensitometric analysis provides a rapid and precise method for the separation and quantitation of both terbinafine hydrochloride and triamcinolone acetonide. The method depends on the quantitative densitometric evaluation of thin layer chromatogram of terbinafine hydrochloride and triamcinolone acetonide at 283 and 238 nm over concentration ranges of 5-25 and 2.5-22.5 microg spot(-1), with mean percentage accuracies 100.66+/-0.51 and 100.27+/-0.73, respectively. The suggested procedures were checked using laboratory prepared mixtures and were successfully applied for the analysis of their pharmaceutical preparations. The three methods retained their accuracy and precision when applying the standard addition technique. The results obtained by applying the proposed methods were statistically analysed and compared with those obtained by a reported method.

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