Range of therapeutic prothipendyl and prothipendyl sulfoxide concentrations in clinical blood samples

Abstract

Due to a lack of reference blood concentrations in the literature, the forensic evaluation of prothipendyl findings in blood samples is difficult. Interpretations with regard to the assessment of blood concentrations as well as an estimation of the ingested prothipendyl amounts were often vague. To describe a concentration range in clinical samples, prothipendyl and prothipendyl sulfoxide concentrations were determined in serum samples of 50 psychiatric patients receiving 40 mg, 80 mg, or 160 mg doses of prothipendyl. The analyses of prothipendyl and prothipendyl sulfoxide were carried out using validated methods of high performance liquid chromatography coupled to triple quadrupole mass spectrometry (LC-QQQ-MS), respectively. 40 mg doses caused average prothipendyl serum concentrations of 18.0 ng/mL (1 hour after intake) and 7.9 ng/mL (10.5 hours after intake), while 80 mg doses caused averages of 42.6 ng/mL and 15.2 ng/mL at the mentioned times of sampling. Irrespective of the given dose, prothipendyl concentrations below 30 ng/mL were observed in 80% of the patient samples taken 1 hour after ingestion as well as in 90% of the samples collected 10.5 hours after administration. Serum concentrations of the Phase I metabolite prothipendyl sulfoxide averaged 4.3 ng/mL (1 hour after intake) and 3.6 ng/mL (10.5 hours after intake). Possible drug-drug interactions regarding absorption and metabolism of prothipendyl are discussed. Results of the herein presented study are useful for the interpretation of analytical prothipendyl findings in forensic toxicology. The utility of the described concentration range is demonstrated by discussing two death cases involving prothipendyl findings.

Intravenous lipid emulsion for a life-threatening prothipendyl intoxication

“…The laboratory alert level is 500 ng/mL 4. The serum concentration of prothipendyl may fluctuate due to factors such as drug-to-drug interactions, delayed absorption and metabolism, prolonged absorption, accumulation, and delayed release of the active compound 5. Only few pharmacokinetic data are available in the literature.…”

“…It may also be explained by the competition between lorazepam, zolpidem, prothipendyl, three lipophilic drugs that may interact with ILE. Finally, a wide range of prothipendyl blood concentrations have been reported and explained by drug-to-drug interaction, absorption and metabolism competition, and redistribution (high volume of distribution) 5…”

Spectrophotometric Assay of Prothipendyl through the Determination of Its Sulfoxide

“…Due to their valuable therapeutic and pharmacological properties, phenothiazine and azaphenothiazine derivatives are the subject of many scientific studies. A review of the literature shows that methods for the determination of phenothiazine and azaphenothiazine derivatives mainly include chromatographic (6)(7)(8)(9) and spectrophotometric (10)(11)(12).…”