Interest of Single Hair Analysis to Document Drug Exposure: Literature Review and a Case Report Involving Zuclopenthixol.

The analysis of hair to detect drugs and drugs of abuse is performed in various contexts, including child protection cases, abstinence control programs, and workplace drug testing. This alternative matrix offers several advantages, such as a large detection window (months) and non-invasive collection. Segmental analysis of multiple hair strands for drugs and metabolites has been widely reported in the literature over the past three decades, whereas a review of the literature showed that there are only 26 articles that report the analysis of a single hair. They focus on two approaches: mass spectrometry imaging techniques, which improve the resolution of dating an intoxication or conventional methods, such as gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (LC-MS/MS). Improved sensitivity of LC-MS/MS techniques allows the evaluation of drug content in segments of a single hair. However, the units used to express the results vary, and depend on the authors. Following a review of the literature, we present a case that illustrates drug analyses both in a strand of hair and a single hair. In this case of exposure of a child to zuclopenthixol (ZPT), the analysis of ZPT in a single segmented hair by LC-MS/MS strengthened the presumption of a single administration.

Flow-injection chemiluminometric determination of some thioxanthene derivatives in pharmaceutical formulations and biological fluids using the [Ru(dipy)3(2+)]-Ce(IV) system.

A flow-injection (FI) methodology using tris(2,2'-dipyridyl)ruthenium(II), [Ru(dipy)3(2+)], chemiluminescence (CL) was developed for the rapid and sensitive determination of three thioxanthene derivatives, namely zuclopenthixol hydrochloride, flupentixol hydrochloride and thiothixene. The method is based on the CL reaction of the studied thioxanthenes with [Ru(dipy)3(2+)] and Ce(IV) in a sulfuric acid medium. Under the optimum conditions, calibration graphs were obtained over the concentration ranges 0.002-6 migrograms/ml for zuclopenthixol hydrochloride, 0.5-15 micrograms/ml for flupentixol hydrochloride and 0.05-7.5 micrograms/ml for thiothixene. The limits of detection (s/n = 3) were 4.2 x 10(-9) mol/l zuclopenthixol hydrochloride, 2 x 10(-8) mol/l flupentixol hydrochloride and 4.5 x 10(-8) mol/l thiothixene. The method was successfully applied to the determination of these compounds in dosage forms and biological fluids.

Voltammetric investigation of oxidation of zuclopenthixol and application to its determination in dosage forms and in drug dissolution studies.

The oxidative voltammetric behaviour of zuclopenthixol (ZPT) at a glassy carbon has been studied using cyclic, linear sweep and differential pulse voltammetry. Oxidation of the drug produced three pH dependent anodic steps (representing an irreversible oxidation). Using differential pulse voltammetry, the drug yielded a well-defined voltammetric response in phosphate buffer, pH 5.2 at + 0.82 V (vs. Ag/AgCl). This process could be used to determine ZPT concentrations in the range 8 x 10(-7)-2 x 10(-4) M. The method was applied, without any interferences from the excipients, to the determination of the drug in tablets and oral drops, and in drug dissolution studies.

Determination of zuclopenthixol and its main N-dealkylated metabolite in biological fluids using high-performance liquid chromatography with post-column photochemical derivatization and fluorescence detection.

A highly sensitive high-performance liquid chromatographic (HPLC) method for the assay of cis-(Z)-clopenthixol (zuclopenthixol) in urine and plasma has been developed. Following solid-phase extraction, the samples are chromatographed using reversed-phase ion-pairing HPLC. After separation, the solutes, having a thioxanthene structure, are transformed on-line into thioxanthones in a photochemical reactor. The thioxanthones are highly fluorescent compounds, and therefore, low detection limits are obtained when using fluorescence detection. Detection limits for zuclopenthixol and its N-dealkylated metabolite, in plasma as well as in urine, using fluorescence detection with excitation at 260 nm and emission at 435 nm, were found to be 0.05 ng/ml and 0.2 ng/ml, respectively. The chromatographic system separates the cis-(Z)- and trans-(E)-isomers of clopenthixol from its main dealkylated metabolite. Furthermore, the chromatographic system is very suitable for study of the photochemical reaction, since the chloro-thioxanthone and thioxanthone are well separated from the isomers of clopenthixol.

Controlling the retention of clopenthixol and other basic drug substances by reversed-phase ion-pair chromatography on bonded-phase materials using two counter-ions of opposite charge.

In the reversed-phase chromatography of nitrogen-containing bases on chemically bonded ODS-silica, peak tailing and prolonged retention are often considerable problems. These effects are due to residual silanols on the surface of the column material and may be remedied by adding suitable amines or quaternary ammonium ions to the eluent as anti-tailing agents. However, further addition of an anionic compound is often needed to achieve a suitable retention. The retention mechanism in such systems is complex as interaction takes place between the anionic compound and the solute molecules, anti-tailing agent and column packing material. The influence of the nature of the anti-tailing agent and anionic counter-ion on the retention of cis- and trans-clopenthixol and of other basic drug substances was investigated and it was found that both the retention and the selectivity were greatly affected.

Milk concentrations of flupenthixol, nortriptyline and zuclopenthixol and between-breast differences in two patients.

Flupenthixol (FP), nortriptyline (NT) and zuclopenthixol, (ZCP) were determined in breast milk and plasma from 2 puerperal, lactating women with psychiatric disorders. The milk concentrations were equal to, higher and lower than those in plasma for FP, NT and ZCP, respectively. Variation in milk triglyceride concentration, but not milk pH, could partly explain between-breast differences in the milk concentrations. The study demonstrates the need for appropriate and representative milk sampling procedures. The estimated daily infant exposure averaged 0.5, 2.3 and 0.3% of the corresponding maternal weight related doses of FP, NT and ZCP. FP was also detectable in infant plasma. These drugs are not known to be harmful in small doses to breast-fed infants. However, concern about the effect of dopamine blocking agents on neurobehavioral mechanisms in animals warrants caution. If neuroleptics are required for a long period this risk must be weighed against the benefits of breast-feeding, also considering the psychological effects of the latter.

Zuclopenthixol levels in serum and breast milk.

Breast milk and serum samples were obtained from six psychotic patients 3 days-10 months after delivery. Five of the women were given zuclopenthixol PO daily, and one was given zuclopenthixol decanoate IM every 2 weeks. Zuclopenthixol was estimated in breast milk and serum by high performance liquid chromatography. The zuclopenthixol levels in milk were found to be 29% of the serum levels on average. Based on the drug levels found in milk, the daily dose to a suckling infant was estimated to be 0.5-5 micrograms zuclopenthixol, corresponding to a dose of 0.01-0.1 mg to an adult. It is not likely that such a low dose would cause any effects or side effects in the infant unless infants are very different from adults concerning metabolism or sensitivity to the drug. The suckling infants included in this study were apparently not influenced by the intake of zuclopenthixol with the milk.