A pharmacokinetic study of ethyl glucuronide in blood and urine: Applications to forensic toxicology

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Abstract

This pharmacokinetic study investigated the kinetics of ethanol and its metabolite ethyl glucuronide (EtG) in blood and urine during the whole time course of absorption and elimination. There are few previous studies on the kinetics of EtG in blood, and we wanted to evaluate whether such knowledge could yield valuable information regarding the time of ethanol ingestion in forensic cases, such as, for instance, drunk driving.

Ten male volunteers consumed ethanol at a fixed dose of 0.5 g/kg body weight in a fasted state. Blood samples were collected for 14 h and urine samples were collected for 45–50 h after the start of drinking.

EtG reached its maximum concentration (Cmax) in blood after a median of 4 h (range 3.5–5), a median of 3 h (range 2–4.5) after Cmax for ethanol. The ethanol-to-EtG ratios in blood (ethanol in g/L, EtG in mg/L) were >1 only for the first median 3.5 h (range 2.5–3.5) after drinking. EtG elimination occurred with a median half-life of 2.2 h (range 1.7–3.1 h), and the renal clearance was 8.32 L/h (median, range 5.25–20.86). The concentrations of EtG were always much higher in urine than in blood. The total amount of EtG excreted in the urine was median 30 mg (range 21.5–39.7), representing 0.017% (median, range 0.013–0.022) of the ethanol given, on a molar basis.

The information from the present study may be a valuable supplement to determine the time of ethanol ingestion. For this purpose, two subsequent increasing EtG values and a high ethanol-to-EtG ratio in blood would support information of recent drinking.

Introduction

Ethyl glucuronide (EtG) is a non-oxidative, minor metabolite of ethanol formed by glucuronidation of ethanol catalyzed by UDP-glucuronosyl transferase [1]. In humans, only a very small amount (about 0.02%) of the ethanol dose consumed is excreted in the urine as EtG [2]. Owing to the markedly prolonged elimination time compared with ethanol itself, measurement of EtG in urine is used as a sensitive and specific biomarker for alcohol intake, and the urinary excretion kinetics are relatively well known through a number of studies [2], [3], [4]. After ingestion of small amounts of ethanol (∼0.1 g/kg body weight), EtG can be detected in urine for 13–20 h (h) [5], [6], and for up to ∼3.5 days after drinking large amounts [7]. Unlike ethanol, the urinary concentration of EtG is highly influenced by urine dilution and could therefore be related to the creatinine content in the sample [2], [8].

The kinetics of EtG in blood is less well known and only one study showed kinetic data of EtG in serum [9]. This study indicated that, after variable doses of ethanol, EtG first became detectable in serum with a lag time of up to 45 min as compared to ethanol. The maximum EtG concentration showed significant inter individual variations and was reached 3.5–5.5 h after alcohol intake, which was 2.0–3.5 h later than for ethanol. Unfortunately, this study only collected blood samples for 8 h, but theoretical calculations indicated that EtG would have remained detectable in blood for up to 17 h [9], [10].

There are several situations where knowledge about the time since ethanol ingestion would be important information. One example is when a subject suspected of drunk driving claims that the ethanol detected in blood results from ethanol consumption after termination of driving (the hip-flask defense) [11]. Even access to two subsequent measures of ethanol in blood can only be used to exclude drinking during the last ∼30 min [12], [13], [14]. The urine-to-blood ethanol ratio has been suggested as another way to help determine the time course of ethanol metabolism, with a value >1 indicating that the subject is in the post-absorptive phase [15]. In forensic cases, such calculations may be complicated, because the urinary ethanol concentration depends on factors that cannot always be controlled for, for example the time since last voiding. Recent drinking can therefore seldom be excluded simply on the basis of ethanol measurements either in blood or urine, and we wondered whether measurement of EtG can become a valuable supplement to ethanol in such cases, if the kinetics of EtG in blood and urine are well known.

This knowledge must be based on sufficient controlled drinking experiments before situations more realistic for drunk drivers can be investigated. The aim of this study was therefore to perform a highly controlled pharmacokinetic study of EtG in blood and urine with minor variations in study parameters.

Section snippets

Study protocol

Ten healthy, male volunteers with a median age of 24 years (range 21–46) and a body mass index of 23.9 kg/m2 (range 20.1–28.3) participated in a controlled experiment. They were all social drinkers with a median use of 32.5 standard drinks/month (range 10–60), and had abstained from alcohol during the week preceding the study, according to self report. Exclusion criteria were somatic or psychiatric illness and use of regular medication.

After an overnight fast, the participants signed in for the

Results

Table 1 summarizes the maximum concentration (Cmax), time of Cmax (Tmax) and the total detection time, for ethanol and EtG in blood and urine, respectively.

Discussion

This controlled, pharmacokinetic study investigated the absorption and elimination characteristics of ethanol and its conjugated metabolite EtG in samples of blood and urine, after healthy, male subjects had ingested a single moderate dose of ethanol (0.5 g/kg) in a fasted state. All subjects involved in this study showed similar time course characteristics for ethanol and EtG, with less inter individual variations compared to a previous publication of EtG in serum [9]. The EtG concentration in

Acknowledgment

To Per Trygve Normann for comments on the manuscript.

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