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EC number: 222-746-8 | CAS number: 3598-16-1
Intravenous injection study:
This study was conducted to characterize the disposition of PE and to determine the absolute topical bioavailability. The average plasma concentration–time profiles of PE and PAA in rats after intravenous injection of PE (doses 0.2, 0.5, and 2 mg/kg) were obtained. After intravenous injection, PE was extensively converted to PAA, with the average PAA-to-PE AUC ratio (AUCPAA/AUCPE) of 5.2, 4.5, and 5.0 for the intravenous doses of 0.2, 0.5 and 2 mg/kg, respectively. The disposition of PE was characterized by a relatively small volume of distribution (Vz, 1.6–2.0 L/kg), high systemic clearance (Cls, 123–132 mL/min/kg), and short terminal half- life (t1/2, 10–11 min). These values remained unaltered as a function of the injected dose range of 0.2–2 mg/kg, indicating a dose-linear kinetics.
Immediately after injection of PE, PAA was formed rapidly, with the time to peak concentration (Tmax) of 9–10 min. For PAA, the average terminal half-life (15–34 min) and Tmax (9 – 10 min) also remained unaltered as a function of the injected dose.
PE was not excreted unchanged in urine, but PAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PE).
Topical application study:
The in vivo percutaneous absorption of PE was characterized in rats after topical application of emulsion and lotion (applied dose of PE = 2.34 mg/kg). Upon topical application, both PE and PAA were quantifiable in the first plasma samples (5 min) and reached Cmax at approximately 1 h. The assay sensitivity was high enough to characterize the initial absorption and terminal elimination processes.
Following topical application, PE was rapidly absorbed and, throughout the sampling period, plasma PAA levels were consistently higher than corresponding PE levels.
The absolute topical bioavailability (F) of PE was high (mean 75.4% and 76.0% for emulsion and lotion, respectively). The apparent terminal half-life of PE found after topical application of emulsion and lotion (mean range, 96–102 min) was significantly longer than that found after intravenous injections (mean range, 10–11 min). Similarly, the apparent terminal half-life of PAA after topical application were significantly longer (108–126 min) than that found after intravenous injections (mean range 15–34 min). These observations indicate that the percutaneous absorption of PE and subsequent formation of PAA are slower than their respective elimination processes. The average AUCPAA/AUCPE ratios following topical application (mean range 4.4–5.3) were comparable to those found after intravenous injection (4.5–5.2). Although the skins are known to contain enzymes (alcohol dehydrogenase and aldehyde dehydrogenase), these comparable AUC ratios suggest that no significant dermal first-pass metabolism of PE occurred during the percutaneous penetration process.
A LC-ESI–MS/MS method with polarity switching was developed and validated. It was applied for the simultaneous analysis of phenoxyethanol (PE) and its major metabolite, phenoxyacetic acid (PAA), in rat plasma, urine, and 7 different tissues. The percutaneous absorption, distribution, metabolism, and excretion were studied in rats.
The absolute topical bioavailability of PE was 75.4% and 76.0% for emulsion and lotion, respectively. Conversion of PE to PAA was extensive, with the average AUCPAA-to-AUCPEratio being 4.4 and 5.3 for emulsion and lotion, respectively.
Immediately after injection of PhE, PhAA was formed rapidly, with the time to peak concentration Tmax of 9–10 min. For PhAA, the average terminal half-life (15–34 min) and Tmax remained unaltered as a function of the injected dose. PhE was not excreted unchanged in urine, but PhAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PhE).
The steady-state tissue-to-plasma PE concentration ratio (Kp) was higher than unity for kidney, spleen, heart, brain, and testis and was lower (≤0.6) for lung and liver, while the metabolite Kp ratio was higher than unity for kidney, liver, lung, and testis and was lower (≤0.3) for other tissues.
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