Update zum Therapeutic Drug Monitoring und zu pharmakogenetischen Untersuchungen zur Optimierung der Therapie mit Psychopharmaka

Das Therapeutic Drug Monitoring von Psychopharmaka wird in zahlreichen Laboratorien immer häufiger durchgeführt, ebenso wie pharmakogenetische Untersuchungen. In diesem Übersichtsartikel wurde die dazugehörige Literatur aus den Jahren 2011 und 2012 zusammengefasst. Die Guidelines der AGNP enthalten alle wichtigen Informationen, die notwendig sind, um Konzentrationen von Psychopharmaka richtig zu interpretieren. Die Bestimmung von Serotonin im Urin könnte ein Marker zur Beurteilung des Therapieerfolgs von Antidepressiva darstellen. Mit Hilfe der Positronen-Emissions-Tomographie konnten Korrelationen zwischen der Belegung der Zielrezeptoren im Gehirn und der Medikamentenkonzentration ermittelt werden. Der Einfluss des Alters auf die Medikamentenkonzentrationen wurde kontrovers beschrieben, wohingegen Frauen in allen Arbeiten bei einigen Antidepressiva einen verlangsamten Metabolismus und erhöhte Serumkonzentrationen aufwiesen. In mehreren Publikationen wurden Multianalytenverfahren für die Bestimmung von Psychopharmaka beschrieben, die trotz unterschiedlicher Methoden sehr gute Validierungsresultate aufwiesen. Bei allen Methoden gibt es einige Substanzen, deren Validationsresultate nur knapp genügten, was auf die Tatsache zurückgeführt werden muss, dass bei Multianalytenverfahren nicht alle Analyten optimal nachgewiesen werden können. Pharmakogenetische Untersuchungen haben noch keinen festen Platz bei der Verordnung von Psychopharmaka. Dies beruht unter anderem auf dem Fehlen von Evidenz-basierten Daten aus großen randomisierten Studien und dem Fehlen von entsprechend standardisierten analytischen Methoden, die die gesamte genetische Variabilität nachweisen könne

Laboratory diagnostics in acute poisoning: critical overview

Laboratory diagnostics play an important role in the treatment of patients with acute poisoning. The classical clinical chemistry and hematology tests help initiate supportive treatment, and specialized methods enable elucidation of the poisons involved. In this context, two different analytical approaches are used: the direct quantification of a potentially involved compound or screening procedures looking either for a distinct drug class or a wide variety of different compounds. The most common tests are immunoassays, which have the advantage of being fast and highly automated. These assays are available for the substances which are often involved in intoxications. The other analytical technique which is widely used is hyphenated chromatography consisting of either high-performance liquid chromatography or gas chromatography as chromatographic systems and detection with a diode-array or mass spectrometer. Whereas gas chromatography mass spectrometry screening procedures have been known for a long time, liquid chromatography mass spectrometry screening methods are now developed by different research groups and still need to prove their reliability. In this review, the different analytical technologies and their application will be discussed. Clin Chem Lab Med 2010;48:1381-

Generation of metabolites by an automated online metabolism method using human liver microsomes with subsequent identification by LC-MS(n), and metabolism of 11 cathinones

Human liver microsomes (HLMs) are used to simulate human xenobiotic metabolism in vitro. In forensic and clinical toxicology, HLMs are popularly used to study the metabolism of new designer drugs for example. In this work, we present an automated online extraction system we developed for HLM experiments, which was compared to a classical offline approach. Furthermore, we present studies on the metabolism of 11 cathinones; for eight of these, the metabolism has not previously been reported. Metabolites were identified based on MS2 and MS3 scans. Fifty-three substances encompassing various classes of drugs were employed to compare the established offline and the new online methods. The metabolism of each of the following 11 cathinones was studied using the new method: 3,4-methylenedioxy-N-benzylcathinone, benzedrone, butylone, dimethylcathinone, ethylone, flephedrone, methedrone, methylone, methylethylcathinone, naphyrone, and pentylone. The agreement between the offline and the online methods was good; a total of 158 metabolites were identified. Using only the offline method, 156 (98.7%) metabolites were identified, while 151 (95.6%) were identified using only the online method. The metabolic pathways identified for the 11 cathinones included the reduction of the keto group, desalkylation, hydroxylation, and desmethylenation in cathinones containing a methylenedioxy moiety. Our method provides a straightforward approach to identifying metabolites which can then be added to the library utilized by our clinical toxicological screening method. The performance of our method compares well with that of an established offline HLM procedure, but is as automated as possibl

Therapeutic drug monitoring by LC-MS-MS with special focus on anti-infective drugs

Liquid chromatography coupled to mass spectrometry nowadays plays an important role in the field of therapeutic drug monitoring (TDM), especially of new compounds for which no immunoassays are available. This paper reviews LC-MS(-MS) methods published recently for anti-infective drugs: antiretroviral drugs, other antiviral drugs, antibacterial drugs, antihelmintic drugs, antimalarial drugs, and other antiprotozoal drugs. An overview of the different methods is given, with special focus on selection of the internal standard and validation procedure

Diagnostic efficiency of different amphetamine screening tests - the search for an optimal cutoff

Increased use of designer drugs (amphetamines and amphetamine-like substances) raises the need for fast screening tests in urine in clinical settings, workplace and drug rehabilitation. Immunological assays currently used are subject to unwanted crossreactivities, partly depending on the cutoff concentrations used. The values recommended in Europe and the USA are 500 and 1000 ng/ml, respectively. In Switzerland, the recommended concentration of 300 ng/ml results in a high rate of false-positive urine samples and expensive, time-consuming confirmation testing. Using the Abbott Axsym analyzer, we found numerous false positives from patients in rehabilitation centers due to concomitant medication. Therefore, the diagnostic sensitivity and specificity of the Abbott test at different cutoff concentrations and the sensitivity of the Roche Cobas Integra, Beckman Synchron and Biosite Triage point-of-care test were examined. HPLC Bio-Rad Remedi was chosen as the method of higher hierarchical order. The specificity of the Axsym analyzer (300 ng/ml) was 86%. At 500 ng/ml or 1000 ng/ml the specificity was increased to 99 or 100%, respectively, while the sensitivity only decreased from 97 to 91 or 81%, respectively. In summary, the cutoff concentration for amphetamine screening tests should not be below 500 ng/ml to avoid a high rate of false-positive result

Development of a fully automated toxicological LC-MSn screening system in urine using online extraction with turbulent flow chromatography

In clinical toxicology, fast and specific methods are necessary for the screening of different classes of drugs. Therefore, an online extraction high-performance liquid chromatography coupled to mass spectrometry (LC-MSn) screening method using a MS2 and MS3 spectral library for the identification of xenobiotic substances has been developed and validated. Samples were run twice, once native and once after enzymatic hydrolysis. Internal standards and buffer were added to the urine samples. Following centrifugation, the supernatant was injected into the system. Extraction was performed by online turbulent flow chromatography. The chromatographic separation was achieved using a Phenyl/Hexyl column. For detection, a linear ion trap, equipped with an APCI interface, was used and the different compounds were identified using a MS2 and MS3 spectral library containing 356 compounds. The turnaround time to report the results of the screening including hydrolysis was approximately 2h. About 92% of the 356 substances could be identified with a limit of identification below 100ng/ml. The recovery and matrix effect experiments showed suitable results, and in six drug-free urine samples of healthy volunteers analyzed for selectivity, no substances have been identified. Carryover could be well controlled, and the method had a good reproducibility. The comparison of the results of 103 real patient urine samples showed a good agreement between the existing GC-MS and LC-MS methods with offline extraction and the new online extraction LC-MSn screening method. The presented method allows a fast and sensitive analysis of a broad range of compound

Monographs on drugs which are frequently analyzed in therapeutic drug monitoring/Arzneimittel-Monographien für Medikamente, die regelmäßig im Rahmen des Therapeutic Drug Monitorings analysiert werden

In addition to the monographs which have been published in the last 6 years by the working group "Drug Monitoring” of the Swiss Society of Clinical Chemistry (SSCC) [Rentsch, Fathi, Grignaschi, Magnin, Printzen, Thormann, J Lab Med 29: 287-97, 2005 - Rentsch, Buhl, Eap, Fathi, Jöchle, Magnin, J Lab Med 34: 129-39, 2010], new monographs have been written. The data presented in these monographs provide an overview of the information which is important for the request and interpretation of the results. Therefore, laboratory health professionals and the receivers of the reports are the targeted readers. With the exception of digoxin, the drugs presented in this series are not administered frequently and are only analyzed in special situations. First, information about pharmacology and pharmacokinetics of these drugs (protein binding, metabolic pathways and enzymes involved, elimination half-life time and elimination route(s) of the parent drug and therapeutic as well as toxic concentrations) is given. Secondly, the indications for therapeutic drug monitoring are listed. Last but not least, important preanalytical information is provided, including time points of blood sampling and time interval after which steady-state concentrations are reached after changing the dose. Furthermore, the stability of the drug and its metabolite(s) after blood sampling are described. For readers with a specific interest, references to important publications are given. The number of the monographs will be further enlarged. The updated files are presented on the homepage of the SSCC (www.sscc.ch). We hope that these monographs are helpful for the better handling of therapeutic drug monitoring and we are looking forward to receiving comments from the readers.

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Background: Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir. Methods: Sixteen healthy volunteers were administered a single oral dose of 1,000mg mebendazole or 400mg albendazole (2 × n = 8). AUC, Cmax, and t1/2 of mebendazole, albendazole, and albendazole sulfoxide were studied in absence and after short-term (2 doses) and long-term (8days) treatment with ritonavir 200mg bid. Results: Pharmacokinetic parameters of albendazole and mebendazole were not changed by short-term administration of ritonavir. However, long-term administration of ritonavir resulted in significant changes in albendazole and mebendazole disposition, with a significant decrease in AUC0-24 (27 and 43% of baseline for albendazole and mebendazole, respectively) and Cmax (26 and 41% of baseline, respectively). Conclusion: The AUC0-24 of benzimidazoles decreased after long-term use of ritonavir, while no changes in pharmacokinetic profiles were observed under short-term administration. These findings might help to optimize benzimidazole efficacy when used in combination with protease inhibitor