Contents lists available at ScienceDirect Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph Providing context for phosphatidylethanol as a biomarker of alcohol consumption with a pharmacokinetic model Ted W. Simon Ted Simon, LLC, 4184 Johnston Road, Winston, GA, 30187, USA ARTICLE INFO Keywords: Alcohol consumption Blood alcohol concentration Phosphatidylethanol PEth 16:0/18:1 Pharmacokinetics ABSTRACT Phosphatidylethanol (PEth) is increasingly used as a biomarker of heavy drinking. Many different forms of PEth can form in red blood cell membranes from the action of the enzyme phospholipase D. PEth has a very long duration in blood because, in contrast to other tissues, RBCs lack the enzymes that degrade PEth. Because this biomarker is relatively new, interpretations of the analytical measurements of PEth may be misinterpreted and the resulting predictions of actual alcohol consumption inaccurate. Hence, a simple pharmacokinetic model of PEth was developed to provide a means of contextualizing these analytical results. A number of alcohol con- sumption scenarios and current clinical screening levels were examined with the model. 1. Introduction Phosphatidylethanol (PEth) is increasingly being recognized as a potential biomarker of chronic alcohol consumption for forensic use (Isaksson et al., 2011). A number of homologues of phosphatidylethanol are formed in the membranes of erythrocytes when alcohol is present. The reaction between ethanol and phosphatidylcholine is catalyzed by phospholipase D (PLD). This enzyme is ubiquitous in mammals; for many years, the function of this enzyme remained unknown; recent knowledge indicates PLD and its normal product, phosphatidic acid, play a role in signaling pathways related to inflammation, cancer pa- thogenesis and neurodegenerative disorders. Phosphatidyl alcohols have varied effects on downstream targets but physiological changes due to altered PLD signaling appear relatively insignificant (Brown et al., 2017). A large number of distinct homologues of PEth form in blood ex- posed to alcohol. The two most abundant are PEth 16:0/18:1 and PEth 16:0/18:2. The homologue generally analyzed by testing laboratories in the US is PEth 16:0/18:1 (Gnann et al., 2010). Estimates of the half-life of PEth 16:0/18:1 and other homologues range from 1 to 13 days and the half-life varies greatly between in- dividuals (Javors et al., 2016). A recent meta-analysis demonstrates good clinical efficiency of PEth for detecting chronic heavy drinking (Viel et al., 2012). The variability in the pharmacokinetics of PEth, however, restricts the ability of this biomarker to predict alcohol con- sumption with any certainty. The choice of a cut-off value is compli- cated by the lack of any quantitative pharmacokinetics to date (Dasgupta, 2015). PEth was first used as a marker of alcohol consumption in the late 1990s; the analytical method was high-performance liquid chromato- graphy with evaporative light scattering detection (HPLC-ELSD); this method could not separate PEth homologues and had a detection limit of almost 600 ng/ml (Hansson et al., 1997; Gunnarsson et al., 1998; Gnann et al., 2009; Varga et al., 1998). In 2009, a method was in- troduced with a much lower detection limit utilizing LC-ESI-MS/MS following miniaturized organic solvent extraction and reversed phase chromatography (Gnann et al., 2009, 2010). Schröck et al. (2014) provide a useful description of analytical methods and a table of de- tection and quantitation limits for the various methods. Differing choices of PEth homologues as alcohol biomarkers as well as the change in analytical methodology with a tenfold lowering of detection limits has created uncertainty regarding the interpretation of PEth results. Weinmann et al. (2016) note: “According to an agreement between Swedish laboratories, the limits of decision for excessive al- cohol consumption has been defined at ≥ 0.3 μmol/l” or 215 ng/ml and these authors refer to the original work in Swedish (Helander and Hansson, 2013). A number of other cutoffs representing varying de- grees of potentially excessive alcohol consumption have been sug- gested. Recent cutoff values are summarized in Table 1 and the range of these cutoffs reflects the varying comparison endpoints, i.e. abstinence vs. moderate drinking vs. drunk driving. The recent interest in devel- oping new cutoffs likely stems from advances in PEth analysis and the comparative advantages of this biomarker (Winkler et al., 2013). Here, an empirically-derived pharmacokinetic model for PEth 16:0/ 18:1 pharmacokinetics is developed and then used to provide context and credible ranges for PEth analytical results corresponding to varying https://doi.org/10.1016/j.yrtph.2018.01.029 Received 26 November 2017; Received in revised form 29 December 2017; Accepted 30 January 2018 E-mail address: ted@tedsimon-toxicology.com. Regulatory Toxicology and Pharmacology 94 (2018) 163–171 0273-2300/ © 2018 Elsevier Inc. All rights reserved. T