Occurrence of psychoactive compounds and their metabolites in groundwater downgradient of a decommissioned sewage farm in Berlin (Germany).

PURPOSE: Psychoactive compounds-meprobamate, pyrithyldione, primidone, and its metabolites, phenobarbital, and phenylethylmalonamide-were detected in groundwater within the catchment area of a drinking water treatment plant located downgradient of a former sewage farm in Berlin, Germany. The aim of this study was to investigate the distribution of the psychoactive compounds in anoxic groundwater and to assess the risk of drinking water contamination. Groundwater age was determined to achieve a better understanding of present hydrogeological conditions. METHODS: A large number of observation and production wells were sampled. Samples were analyzed using solid-phase extraction and ultrahigh-performance liquid chromatography-tandem mass spectrometry. Groundwater age was estimated using the helium-tritium ((3)He-(3)H) dating method. RESULTS: Concentrations of psychoactive compounds up to 1 µg/L were encountered in the contamination plume. Generally, concentrations of phenobarbital and meprobamate were the highest. Elevated concentrations of the analytes were also detected in raw water from abstraction wells located approximately 2.5 km downgradient of the former sewage farm. Concentrations in the final drinking water were below the limit of quantification owing to dilution. The age of shallow groundwater samples ranged from years to a decade, whereas groundwater was up to four decades old at 40 m below ground. Concentrations of the compounds increased with groundwater age. CONCLUSIONS: Elevated concentrations of psychoactive drugs indicate a strong persistence of these compounds in the environment under anoxic aquifer conditions. Results suggest that the heritage of sewage irrigation will affect raw water quality in the area for decades. Therefore, further monitoring of raw and final drinking water is recommended to ensure that contaminant concentrations remain below the health-based precautionary value.

Quantitative simultaneous determination of eight common antiepileptic drugs and metabolites by liquid chromatography.

Specific antiepileptic drug (AED) concentrations in serum are believed to cause therapeutic effects in individual patients. Communication between the clinician and the laboratory performing the drug level determinations is therefore essential for safe and effective medication. The now common practice of multiple drug therapy preferably requires simultaneous separation and quantitation of the various drugs and their metabolites. The advantages and disadvantages of current AED analysis methods are discussed. Liquid chromatography (LC) was found to be the most versatile technique for routine and research analysis and can be applied to the determination of common, less common and new AED and metabolites. Carbamazepine and its metabolite, carbamazepine-10,11-epoxide, were determined with high accuracy. The sample preparation procedures, the internal standards, and mode of LC separation used for the analysis are given. The chromatographic parameters for optimized resolution and analysis are given. The chromatographic parameters for optimized resolution and analysis time of eight AEDs and metabolites were devised with special consideration for the influence of the oven temperature on resolution. About 300 patient serum samples were analyzed by automatic unattended operation. By this method some 50 samples per day can be extracted and analysed. Quantitative results achieved by LC and gas liquid chromatography (GLC) on the same patient samples are reported and chromatograms discussed. Peak scanning was used to demonstrate the presence of compounds which could eventually interfere with the detection of phenylethylmalonamide. The overall accuracy of the employed LC method, the repeatability of retention times on three different columns, and the measured ranges of AED concentrations are reported.

Microassay for primidone and its metabolites phenylethylmalondiamide, phenobarbital and p-hydroxyphenobarbital in human serum, saliva, breast milk and tissues by gas chromatography--mass spectrometry using selected ion monitoring.

A method for the quantitative determination of primidone and its metabolites phenobarbital, phenylethylmalondiamide (PEMA) and hydroxyphenobarbital (free and conjugated) in serum, urine, saliva, breast milk and tissue has been developed. Following the addition of the methyl analogues of primidone, phenobarbital and PEMA as internal standards and of saturated ammonium sulphate, the samples (5--100 microliter) were extracted twice with ethyl acetate--benzene (20:80). The extracts were divided into two equal portions; one portion was ethylated by Greeley's method for the analysis of primidone, phenobarbital and hydroxy-phenobarbital, while the other was trimethylsilylated for the analysis of primidone and PEMA. A gas chromatographic--mass spectrometric system was used for the analysis of the derivatized extracts. Linear calibration curves were obtained in the concentration range studied (between 100 ng/ml and 30 microgram/ml). The recoveries of the drugs were between 80 and 93%. The relative standard deviations were between 3.2 and 5.9% (100-microliter serum samples containing 1 microgram/ml of the drugs). The lower detection limits were found to be between 1.4 and 3.7 ng/ml using serum samples of 100 microliter. These methods have been applied to the study of the placental transfer and neonatal disposition of primidone and its metabolites in the human.

Single-dose pharmacokinetics and anticonvulsant efficacy of primidone in mice.

The pharmacokinetics and efficacy of the anticonvulsant primidone (PRM) and its active metabolites, phenobarbital (PB) and phenylethylmalonamide (PEMA), were studied after single-dose administration in mice. The half-life of PB is twice that of PRM and PEMA. The plasma/brain ratios provide evidence of poor penetration of PRM into brain. The results support our findings of negligible or absent PRM concentrations in the brains of patients on primidone therapy who were undergoing surgery for intractable epilepsy. The anticonvulsant properties of PRM, PB, and PEMA against maximal electroshock in mice were also studied with the use of the metabolic inhibitor SKF 525A. The half-life, potency, peak anticonvulsant effect, and effective dose curves of these compounds indicate that the anticonvulsant effect of short-term oral PRM administration in mice is from derived PB.