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Abstract
Analysis of in vitro samples with high salt concentrations represents a major challenge for fast and specific quantification with liquid chromatography-tandem mass spectrometry (LC-MS/MS). To investigate the intestinal permeability of opioids in vitro employing the Ussing chamber technique, we developed and validated a fast, sensitive and selective method based on LC–MS/MS for the determination of loperamide in HEPES-buffered Ringer's solution. Chromatographic separation was achieved with an Atlantis dC18 column, 2.1 mm×20 mm, 3 µm particle size and a gradient consisting of methanol/0.1% formic acid and ammonium acetate. The flow rate was 0.7 ml/min, and the total run time was 3 min. For quantification, two mass transitions for loperamide and a deuterated internal standard (methadone-d3) were used. The lower limit of loperamide quantification was 0.2 ng/ml. This new LC-MS/MS method can be used for the detection of loperamide in any experimental setup using HEPES-buffered Ringer's solution as a matrix compound.
Highlights
Opioids have been viewed as prototypes of centrally acting analgesics
Animal studies have demonstrated that a large proportion (50–100%) of the antinociceptive effects produced by systemically administered opioids can be mediated by peripheral opioid receptors [2,3,4,5,6,7] and human studies indicate that opioid agonists that do not readily enter the central nervous system (CNS) can have the same analgesic efficacy as conventional opioids [8]
We aim to use liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)
Summary
Opioids have been viewed as prototypes of centrally acting analgesics. Animal studies have demonstrated that a large proportion (50–100%) of the antinociceptive effects produced by systemically administered opioids can be mediated by peripheral opioid receptors [2,3,4,5,6,7] and human studies indicate that opioid agonists that do not readily enter the central nervous system (CNS) can have the same analgesic efficacy as conventional opioids [8]. Loperamide has low oral bioavailability because of its low absorbance rate from the gut It does not readily pass the blood brain barrier because it is a substrate of the efflux membrane transporter P-glycoprotein (P-gp) [11,12]. To eventually reach opioid receptors in peripheral inflamed tissues, orally administered loperamide must first permeate the intestinal epithelium and enter the blood stream
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