Research ArticlePharmacokinetics, Pharmacodynamics and Drug Transport and MetabolismPharmacokinetics in Elderly Women of Benzyl Alcohol From an Oil Depot
Introduction
Benzyl alcohol (BOH) is a commonly used excipient in oil depots in a concentration range of 1.5%-10% vol/vol.1, 2, 3, 4 It is used as cosolvent, local anesthetic, and as viscosity reducer in oil depots.5 In other parenteral pharmaceutical products and in cosmetics, it is used as an antimicrobial preservative in concentrations varying from 1%-10% vol/vol.5, 6, 7 Oil depots are meant to exhibit extended release of (active) substances.
Usually, these depots are administrated in muscular or subcutaneous tissue. Both tissues contain aqueous interstitial fluid in which the active substance and BOH are released. Although BOH is nearly always used in oil depots, there are no publications available on the release of this excipient from these formulations or on the effect of this toward the release of the drug. Recently, Kalicharan et al.8 showed that the absorption of (active) substances from depots is determined by the partition coefficient. Because BOH changes solubility of components in both the oil and the body fluid, the distribution of (active) substances between the oil and body fluid may alter during BOH release. As a result, the absorption of these substances can be influenced during BOH release and is therefore clinically relevant.
When BOH is released from the depot, it is metabolized into benzoic acid (BA).9 In the liver, BA is subsequently conjugated with glycine to form hippuric acid (HA).10, 11 Table 1 gives a summary of the mentioned substances.
It is important to realize that BA is also processed as such as a preservative in pharmaceutical products5 and in food.12, 13 As there may be another source of BA than the BOH released out of the depot, it is therefore meaningful to measure the levels of BOH and its metabolites simultaneously. Until now, no analytical methods are available to separate these compounds in human serum. The HPLC method published by Tan et al.14 to determine BOH, BA, and HA simultaneously in dog plasma was not applicable for human serum, based on our own research. This was the reason to start the development of a bioassay to determine the components of interest in human serum.
The aim of this study was to determine the pharmacokinetic profiles of BOH and its metabolites BA and HA in serum to estimate the BOH release out of the depot. This was achieved with an appropriate analytical method that enables determination of the parent and its metabolites simultaneously.
Section snippets
Chemicals and Reagents
BOH, BA, HA, benzocaine (internal standard, IS), and 1 M triethylammonium phosphate (pH 3.0) buffer solution were purchased from Sigma-Aldrich (St. Louis, MO). HPLC-grade methanol, acetonitrile, and perchloric acid were obtained from Merck (Darmstadt, Germany). Newborn calf serum was purchased from Life Technologies (Carlsbad, CA).
HPLC Equipment and Conditions
The separation of the analytes and IS was carried out with an isocratic HPLC method. Based on a published method by Tan et al.,14 benzocaine (Table 1) was selected as
Results and Discussion
This study was initiated to develop and validate a bioassay for BOH, BA, and HA in human serum by HPLC. Hereafter, this assay was applied to serum samples from healthy volunteers to study the pharmacokinetic profiles of BOH and its metabolites.
Conclusions
This article reports the development of an assay for simultaneous determination of BOH, BA, and HA in human serum by HPLC. The assay is tested and validated to conform to the latest ICH Q2(R1) guideline and EMA Guideline for bioanalytical method validations. It appears to be accurate, selective, sensitive, and reproducible for BOH, BA, and HA in human serum. The sample pretreatment is simple to perform because no preconcentration, derivatization, or extraction procedures are required. In
Acknowledgments
Funding: Utrecht University, The Netherlands.
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Conflicts of interest: The authors declare that there are no conflicts of interest.
This article contains supplementary material available from the authors by request or via the Internet at http://dx.doi.org/10.1016/j.xphs.2016.01.022.