Development of a highly sensitive LC–MS/MS method for simultaneous determination of rupatadine and its two active metabolites in human plasma: Application to a clinical pharmacokinetic study

• An assay method of rupatadine with two metabolites in human plasma was developed.
• First report to investigate the back-conversion of two metabolites of rupatadine.
• LLOQ between 0.035–0.05 ng/mL for rupatadine and its metabolites was obtained.
• First report comparing PK profile between single and multiple doses of rupatadine.
• First report comparing PK profile between male and female dosed with rupatadine.

An easy LC–ESI–MS/MS method was developed and validated for simultaneous determination of rupatadine (RT) and its two active metabolites, namely desloratadine (DT) and 3-hydroxydesloratadine (3-OH-DT), in human plasma. The chromatographic separation was carried out on a C18 column with gradient elution by using methanol and 10 mM ammonium acetate containing 0.1% (v/v) formic acid. The lower limit of quantification (LLOQ) was 0.05, 0.035 and 0.035 ng/mL for RT, DT and 3-OH-DT, respectively. The intra- and inter-day precision of analytes were within the range of 1.0–4.7% and 2.2–12.1%, respectively. The intra- and inter-day accuracy of analytes were within the range of −7.7% to 5.2% and −4.1% to 4.8%, respectively. The method was successfully applied to a pharmacokinetic study of RT and its two metabolite DT and 3-OH-DT in healthy volunteers following single (10, 20, 40 mg) and multiple (10 mg) oral doses of rupatadine fumarate tablets.

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