Absorption, Pharmacokinetics, and Safety of Triclosan after Dermal Administration

Abstract

We evaluated the pharmacokinetics and safety of the antimicrobial agent triclosan after dermal application of a 2% triclosan-containing cream to six volunteers. Percutaneous absorption calculated from urinary excretion was 5.9% ؎ 2.1% of the dose (mean ؎ standard deviation). The amount absorbed suggests that daily application of a standard adult dose would result in a systemic exposure 890 times lower than the relevant no-observed-adverse-effect level. Triclosan can be considered safe for use in hydrophobic creams.Triclosan is an antimicrobial agent with broad-spectrum activity against Gram-positive and Gram-negative bacteria as well as some molds and yeasts. It is bacteriostatic at low concentrations as it blocks lipid synthesis, whereas at higher concentrations (as reached in dermatological preparations) membrane destabilization and triclosan-induced K ϩ leakage lead to a rapid bactericidal effect (9, 16). Furthermore, triclosan potently inhibits the growth of Toxoplasma gondii and Plasmodium (13,20) and shows anti-inflammatory effects after topical administration (11,19).For more than 20 years, triclosan has been used widely worldwide in medical and consumer products (5, 21). In dermatological preparations, it is an effective topical antiseptic to reduce colonization with Staphylococcus aureus and to treat superinfected atopic dermatitis (2,8,10,22). Despite the almost-ubiquitous occurrence of the substance, pharmacokinetic studies are sparse.We evaluated the pharmacokinetics and safety of triclosan in a clinical study in six healthy Caucasians. The study was approved by the Ethics Committee of the University of Cologne and by the competent German authorities, and all participants gave their written informed consent. Demographic baseline characteristics are shown in Table 1. The study medication (provided by Infectopharm) was a hydrophobic cream containing 2% triclosan. Its composition corresponds to a dermatological standard preparation (NRF 11.122) which is listed in the Neues Rezeptur Formularium (German List of Recommended Standard Formulations). Approximately 60 g of the cream was massaged into the skin of the whole body except for the head and genitals. Exposure was ended by taking a shower 12 h after administration. The subjects were confined to the clinical ward under standardized conditions from 10 h prior until 48 h after study drug administration.Urinary excretion during individual sampling intervals up to 168 h postdose was used for pharmacokinetic calculations (WinNonlin version 5.01). For quantification, the sum of free triclosan and its glucuronide and sulfate metabolites (after enzymatic hydrolysis) was determined using a specific and sensitive high-performance liquid chromatographymass spectrometry approach based on published methods (15, 18). The lower and upper limits of quantification were 4.5 and 800 g/ml, respectively. Quality control samples showed good precision and accuracy throughout the measurement of study samples.In all individuals, the major fraction of absorbed triclosan was exc...

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