An analytical strategy to characterize the pharmacokinetics and pharmacodynamics of triptorelin in rats based on simultaneous LC–MS/MS analysis of triptorelin and endogenous testosterone in rat plasma

Abstract

Triptorelin, a gonadotropin-releasing hormone agonist, has been used in the treatment of hormone-responsive prostate cancer by inducing testosterone suppression. Research on the relationship between the time courses of triptorelin and testosterone is very important, but accurate quantification of triptorelin and testosterone simultaneously in biological specimens is a challenging analytical problem. In the present study, a rapid, sensitive, and selective method for simultaneous determination of triptorelin and testosterone in rat plasma by solid-phase extraction and liquid chromatography-tandem mass spectrometry was developed using a ZORBAX RRHD Eclipse Plus C8 column (2.1 × 50 mm, 1.8 μm) with a 0.05% propionic acid/methanol gradient. In view of the polarity difference between the two analytes, two internal standards, i.e., leuprolide and testosterone-(13)C3, were used for individual quantitation of triptorelin and testosterone. Endogenous testosterone was determined by reference to a calibration curve prepared using testosterone-D3 as a surrogate analyte. The method exhibits excellent linearity over three orders of magnitude for each analyte. The lower limit of quantification was 0.01 ng/mL for triptorelin and 0.05 ng/mL for testosterone, with consumption of 100 μL of plasma. The method was successfully applied to characterize the pharmacokinetics and pharmacodynamics of slow-release 28-day form triptorelin acetate biodegradable microspheres in rats after intramuscular injections of three consecutive doses of 0.6 mg/kg per 28 days. The results revealed that the pharmacokinetic profile of triptorelin produced an initial flare-up in testosterone levels, rapid castration within 5 days after injection, and long-term castration until the next dose.

Capillary Electrophoresis–Mass Spectrometry with Multisegment Injection and In-Capillary Preconcentration for High-Throughput and Sensitive Determination of Therapeutic Decapeptide Triptorelin in Pharmaceutical and Biological Matrices

“…Two most abundant characteristic ions, i.e., quantifier (ion with the highest intensity, m/z = 328.3) and qualifier (m/z = 249.0), were selected from the mass spectrum (Figure 1b). The selected product ions are in good agreement with the previous papers dealing with MS analyses of triptorelin [24,25].…”

“…Table 6 provides a summary of chromatographic and electrophoretic methods used for determination of triptorelin in biological samples, i.e., plasma, serum, and urine. Determination of triptorelin has been typically performed with the use of liquid chromatography (LC) coupled with MS [25,[42][43][44][45][46][47] or UV detection [48,49]. Actually, the only CE method developed for biological samples is this one presented in our work.…”

Pharmacokinetic–Pharmacodynamic Model for the Testosterone-Suppressive Effect of Leuprolide in Normal and Prostate Cancer Rats

“…The plasma concentrations of testosterone profiles after IV and SC administration of leuprolide solution and the Lucrin depot ® are shown in Figure 2 . In the leuprolide solution and SR depot-administered group with or without prostate cancer (Groups 1, 3, 4, and 6), all the groups showed the “flare-up effect” [ 14 ], when the concentration of testosterone is dramatically increased. The maximal peak of testosterone level in each group, caused by the flare-up effect, was similar at 2 h after administration.…”

Triptorelin relieves lower urinary tract symptoms in Chinese advanced prostate cancer patients: a multicenter, non-interventional, prospective study

“…Triptorelin is an agonist of natural GnRH with increased duration of action and higher affinity for the pituitary receptor compared with the parent compound [ 7 ]. It downregulates GnRH receptors and causes a post-receptor desensitization of gonadotrophic cells, resulting in reversible biochemical castration [ 8 ]. After initial stimulation, gonadotropin secretion is inhibited by prolonged administration of triptorelin, thereby suppressing testicular function [ 9 ].…”