Development and validation of a sensitive liquid chromatographic–tandem mass spectrometric method for the simultaneous analysis of granisetron and 7‐hydroxy granisetron in human plasma and urine samples: application in a clinical pharmacokinetic study in pregnant subject

Abstract

A liquid chromatography-tandem mass spectrometric method for the quantification of granisetron and its major metabolite, 7-hydroxy granisetron in human plasma and urine samples was developed and validated. Respective stable isotopically labeled granisetron and 7-hydroxy granisetron were used as internal standards (IS). Chromatography was performed using an Xselect HSS T3 analytical column with a mobile phase of 20% acetonitrile in water (containing 0.2 mM ammonium formate and 0.14% formic acid, pH 4) delivered in an isocratic mode. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used for quantification. The standard curves were linear in the concentration ranges of 0.5-100 ng/mL for granisetron and 0.1-100 ng/mL for 7-hydroxy granisetron in human plasma samples, and 2-2000 ng/mL for granisetron and 2-1000 ng/mL for 7-hydroxy granisetron in human urine samples, respectively. The accuracies were >85% and the precision as determined by the coefficient of variations was <10%. No significant matrix effects were observed for granisetron or 7-hydroxy granisetron in either plasma or urine samples. Granisetron was stable under various storage and experimental conditions. This validated method was successfully applied to a pharmacokinetic study after intravenous administration of 1 mg granisetron to a pregnant subject.

Ondansetron Exposure Changes in a Pregnant Woman

“…Serial blood samples were collected over one 8‐hour dosing interval at time 0 and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after dosing, at 14, 24, and 35 weeks’ gestation (representing early‐, mid‐, and late‐pregnancy time points, respectively). Plasma concentrations of ondansetron were measured based on minor modification of a previously published liquid chromatography–tandem mass spectrometric assay using a Waters Separation Module 2695 and a Waters Micromass Quattro micro triple quadrupole mass spectrometer (Waters Corp., Milford, MA) using positive electrospray ionization mode. Steady‐state ondansetron peak plasma concentrations ( C max ) and area under the plasma concentration–time curve from 0 to 8 hours (AUC 0–8 ) declined across gestation (Table , Figure ).…”

Polymorphisms inCYP1A1andCYP3A5Genes Contribute to the Variability in Granisetron Clearance and Exposure in Pregnant Women with Nausea and Vomiting

“…Blood was collected from the opposite arm of the IV infusion at baseline and at 10 #bib20 #bib30, and 60 minutes and 2 #bib4 #bib6 #bib8 #bib12, and 24 hours after completion of the IV infusion. Plasma concentrations of granisetron and 7‐hydroxy granisetron were determined simultaneously using a liquid chromatography–tandem mass spectrometry (LC‐MS/MS)–based method developed in our laboratory . Noncompartmental analysis was used to estimate the area under the plasma concentration x time curve from time zero to infinity (AUC 0–∞ ) and clearance of granisetron using WinNonlin version 5.2 (Certara, Princeton, NJ).…”