Inflammation affects the pharmacokinetics of risperidone: Does the dose need to be adjusted during the acute-phase reaction?

BACKGROUND: Several studies have indicated that the plasma concentration of risperidone increases 3-5-fold during the acute-phase reaction (APR) of inflammation or infection. Psychiatric symptoms are present or deteriorate when the dose is lowered; thus, the complex effects of inflammation on the pharmacokinetics of risperidone need to be examined. METHODS: We established a APR model in rabbits induced by lipopolysaccharide (LPS) and studied the effect of APR on pharmacokinetics, distribution and disposition of risperidone in vivo and in vitro. RESULTS: Following intramuscular administration, the plasma exposures for risperidone and its active metabolite (9-hydroxyrisperidone) were increased approximately 6-fold on day 2 of inflammation. The exposure values did not change between day 2 and 5 of inflammation, nor did the metabolite-to-parent ratio before and during inflammation. Following oral administration, the increase of risperidone exposure was twice as high as that following intramuscular administration during APR. However, the concentration of risperidone and 9-hydroxyrisperidone in brain tissue was similar between the inflammatory and control groups. Moreover, the plasma protein binding (PPB) of risperidone and 9-hydroxyrisperidone associated with inflammation were all increased to >99 %. In addition, risperidone and 9-hydroxyrisperidone were not substrates of the key transporters, OATP1B3, OCT2, OAT3, MATE-1, or MATE-2 K. The expression of progesterone X receptor and P-glycoprotein was inhibited by LPS. CONCLUSION: During APR, reduced expression of P-glycoprotein and increased PPB were responsible for increased exposure in plasma, while maintaining stable concentrations in the brain, and risperidone does not need to be dose-adjusted so as to achieve psychopharmacological outcomes.

Optimization and validation of the liquid chromatography coupled to tandem mass spectrometry method for assessing octreotide release from microspheres during inflammation in rabbit models.

To study the effect of acute-phase reaction (APR) of inflammation on the release of octreotide acetate microsphere (Sandostatin®, SLAR) at a clinical dose, a more sensitive liquid chromatography coupled to tandem mass spectrometry analysis method needs to be developed because of the low plasma concentrations of octreotide. Solid-phase microextraction with an Oasis® HLB µElution plate was adopted for sample preparation. Extraction recovery ranged from 65.7 % to 73.2 %, and the matrix effect was negligible. High sensitivity and an intense chromatographic peak were acquired by optimizing the chromatography and mass spectrometry conditions. The lower limit of quantitation (LLOQ) was 0.01 ng/mL based on 100 µL of plasma, and linearity ranged from 0.01 to 5.0 ng/mL. The coefficients of variations for intraday and interday precision were less than 4.4 %, and the relative error of accuracy was within 5.7 %. The validated method was successfully applied to pharmacokinetics studies of SLAR in a seven-day inflammation model of rabbits, indicating that the APR did not affected the release and pharmacokinetics of the octreotide microspheres.