Simultaneous determination of prochlorperazine and its metabolites in human plasma using isocratic liquid chromatography tandem mass spectrometry

Abstract

Oral prochlorperazine (PCZ), an antiemetic, undergoes extensive first-pass metabolism. The study developed a simultaneous analytical method for PCZ and its major metabolites, prochlorperazine sulfoxide (PCZSO), N-demethylprochlorperazine (NDPCZ) and 7-hydroxyprochlorperazine (PCZOH), in human plasma using an isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Deproteinized plasma specimens were separated using a 3 µm particle size octadecylsilyl column, and the run time was 10 min. The calibration curves were linear over the concentration ranges of 0.01-40 µg/L for PCZ, NDPCZ and PCZOH, and 0.05-80 µg/L for PCZSO. The intra- and inter-assay precisions and accuracies were within 7.0 and 99-104% and within 9.0 and 99-105%, respectively. The lower limits of quantification in human plasma were 10 ng/L for PCZ, NDPCZ and PCZOH, and 50 ng/L for PCZSO. The validated method was applied to the determination of plasma samples in 37 cancer patients receiving PCZ. Large interindividual variations were observed in plasma concentrations of PCZ, PCZSO, NDPCZ and PCZOH (relative standard deviation, 89.4, 88.7, 86.4 and 78.2%, respectively). In conclusion, this simultaneous LC-MS/MS method with acceptable analytical performance can be helpful for evaluating the pharmacokinetics of PCZ, including the determination of its metabolites in cancer patients and in clinical research.

Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites and their relationships with clinical responses in cancer patients

“…Plasma concentrations of PCZ and its metabolites were determined by LC-MS/MS as previously described. 2 The calibration curves in human plasma were linear over the concentration ranges of 0.01-40 ng/mL for PCZ (r > 0.999), NDPCZ (r > 0.999), PCZOH (r > 0.999) and 0.05-80 ng/mL for PCZSO (r > 0.999). Their intra-and inter-assay precisions and accuracies were within 5.8% and 100-104% and within 7.8% and 99%, respectively.…”

“…1 The pharmacokinetics and pharmacodynamics of PCZ showed a large variation in cancer patients. 2 PCZ is extensively metabolized in the intestine and liver by cytochrome P450 (CYP) and has low oral bioavailability due to a large first-pass effect. 3 Recent studies have demonstrated that CYP2C19, CYP2D6 and CYP3A4/5 are the major CYP isozymes involved in the metabolization of PCZ.…”

Analytical review of Prochlorperazine side effects and acute poisonings

“…Так, відповідно до даних джерел для визначення та оцінки прохлороперазину у формі субстанції та лікарських форм авторами використано ряд аналітичних методів для ідентифікації та кількісного визначення при проведенні фармацевтичного аналізу, вивчення фармакокінетики, дослідження біоеквівалентності. Зокрема, гравіметричний [35], спектрофотометричний [35,36], ТШХ [37], ВЕРХ [38][39][40][41], кондуктометричний [42], вольтамперометричний [43], капілярний електрофорез [44], РХ-MС методи [45,46].…”