## 1 Introduction  
Ketamine (KET) was developed in 1962 during a search for a less problematic replacement for phencyclidine (PCP), an anesthetic that had gained notoriety for inducing hallucinations and psychosis. Due to its quick onset and short duration of action with only slight cardio-respiratory depression in comparison with other general anesthetics and the possibility of inhalation to maintain the anesthetic state, KET is a preferred drug for short-term surgical procedures in veterinary and human medicine, especially in children [1]. The main drawback of KET is its potential for causing vivid hallucinations, similar to those described for lysergic acid diethylamide (LSD) consumption [2]. As a result of this, it was initially abused by medical personnel and gradually became popular among young users at dance and rave parties [3]. In fact, the total quantity of KET seized worldwide increased from an annual average of 3 tons in the period 1998-2008 to 10 tons in the period 2009-2014 and 15 tons annually between 2015 and 2017 [4]. In humans, KET is metabolized in the liver by the microsomal cytochrome P450 system. CYP3A4 is the main enzyme responsible for KET \(N\)-demethylation to form norketamine (NKET). NKET is then hydroxylated, conjugated and excreted in the urine [5]. Studies of KET urinary excretion indicate that, over a 72-h period, little unchanged drug and NKET are present (2.3% and 1.6%, respectively). Most excreted compounds (80%) are conjugates of hydroxylated KET metabolites [6]. In urine collected from hospitalized children who had received KET as an anesthetic, it was detectable up to 2 days after drug administration (29-1410 \(\upmu\)g L\({}^{-1}\)) and NKET was detected for up to 14 days (up to 1559 \(\upmu\)g L\({}^{-1}\)) [7]. In a group of presumed recreational KET users, urine concentrations of KET and NKET were 6-7744 \(\upmu\)g L\({}^{-1}\) and 7-7986 \(\upmu\)g L\({}^{-1}\), respectively [8].  
Several analytical methods have been described in the literature for the determination of KET or NKET in urine samples, mostly using high performance liquid chromatography with ultraviolet/visible detection (HPLC-UV) [9], gas chromatography (GC) coupled to either flame ionization detector (FID) [10], mass spectrometry (MS) [3; 7; 11], _Tandem_ mass spectrometry (MS/MS) [12] or even liquid chromatography (LC) coupled to MS [7; 8] or MS/MS [13; 14]. Sample preparation techniques used in combination with these chromatographic or hyphenated systems include conventional liquid-liquid extraction (LLE) [8] or solid-phase extraction (SPE) [7; 14; 15], but also miniaturized techniques such as solid-phase microextraction (SPME) [16], stir bar sorptive extraction [9], hollow-fiber liquid-phase microextraction [3; 10] or microextraction by packed sorbent (MEPS) [12]. However, the preparation and manipulation of these techniques are tiresome, and the number of possible simultaneous microextractions are very limited, especially when routine work is involved. In order to overcome some of these issues we recently introduced an alternative approach, high-throughput bar adsorptive microextraction (HT-BA\(\upmu\)E) [17]. This new technique and apparatus have shown to be user-friendly, cost-effective and presented remarkable effectiveness as a rapid tool for the simultaneous microextraction of up to 100 samples. In the present work, we propose the use of HT-BA\(\upmu\)E for the extraction process and subsequent microliquid desorption of up to 100 samples in combination with large volume injection-gas chromatography-mass spectrometry operating in the selected-ion monitoring acquisition mode (HT-BA\(\upmu\)E-\(\upmu\)LD/LVI-GC-MS(SIM)) for the determination of KET and NKET in urine matrices. To our knowledge this is the first work that reports the use of a miniaturized high throughput methodology for the analysis of the target compounds in urine matrices.