Background Loratadine (LTD) is a Biopharmaceutical Classification System II basic drug with pH-sensitive aqueous solubility and dissolution is a speed-limiting step of its absorption. The drug dissolution and the gastrointestinal tract pH conditions are likely to influence the in vivo pharmacokinetic behavior of LTD tablets. Materials and Method A rapid, sensitive, and reliable bioanalytical method for simultaneous quantitation of LTD and its active metabolite desloratadine (DL) in beagle plasma was developed and validated based on liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample preparation in low plasma consumption was accomplished by liquid–liquid extraction. The chromatographic separation was achieved on a Phenomenex Kinetex C8 column using acetonitrile and 5 mM ammonium formate as the mobile phase. A comparative pharmacokinetics study of three LTD tablets with different dissolution rates was conducted in male beagles in fasting state and an omeprazole-induced drug–drug interaction (DDI) study was subsequently performed under pretreatment of omeprazole. Results and Conclusion The method showed a good linear correlation over the concentration ranges of 0.008–24 ng/mL for LTD and 0.8–800 ng/mL for DL, and was successfully applied to analyze the two compounds in beagle plasma. Pharmacokinetic results showed in the fasting state the three LTD tablets were equivalent in beagles in terms of effective components. DL of the three tablets were equivalent, indicating metabolite was less susceptible to pharmaceutic preparation factors for LTD tablets in beagles. Moreover, significant changes in LTD and DL pharmacokinetics parameters were observed under the effect of omeprazole-induced pH increase in gastrointestinal tract, suggesting that DDI effects are of concern for the curative effect of LTD when combined with omeprazole. The findings will contribute to the future pharmaceutical preparations research as well as the clinical application of LTD.

A valine carbamate prodrug of naringenin (NAR) called 4'V was synthesized to enhance its oral bioavailability because of low water solubility and poor membrane permeability of NAR. This study developed and fully validated a sensitive, rapid, and robust HPLC-MS/MS method for the simultaneous determination of NAR and 4'V in plasma. The analytes were treated using liquid-liquid extraction, separated on a Phenomenex Kinetex XB-C 18 column, and detected using a triple-quadrupole tandem mass spectrometer equipped with an electrospray ionization interface. The analytes were eluted within only 4 min by gradient procedure. The excellent linear correlations were validated over the range of 4-400 ng/mL (r = 0.9990) for NAR and 2-2000 ng/mL (r = 0.9951) for 4'V, with lower limits of quantification of 4 and 2 ng/mL, respectively. For all quality control samples, the intra-day and inter-day precision and accuracy were within ±15%. The validated method was economical, high throughput, and reliable and was first successfully applied to a pharmacokinetic study of NAR and 4'V after oral administration to Sprague-Dawley rats. The results of the pharmacokinetic study demonstrated that the idea of amino acid carbamate prodrug is a promising strategy to improve the bioavailability of NAR.

The naturally occurring linear dipeptide JBP923 (trans-4-L-Hyp-L-Ser, HS-tLL) with anti-inflammatory effects showed potential for the treatment of inflammatory bowel disease (IBD). However, colon-specific delivery after oral administration is still a challenge because its absorption is mediated by oligopeptide transporter 1 (PEPT1) in the upper small intestine and because of its instability in the gastrointestinal tract. Therefore, we aimed to enhance the colon-targeting efficiency by modulating HS-tLL chirality to synthesize eight enantiomers. Among these enantiomers, trans-4-D-Hyp-D-Ser, cis-4-L-Hyp-D-Ser, cis-4-D-Hyp-L-Ser, and cis-4-D-Hyp-D-Ser did not work as substrates of PEPT1 and were stable in the gastrointestinal tract, resulting in enhanced colonic accumulation through the paracellular pathway due to the loose tight junctions in IBD. Interestingly, cis-4-D-Hyp-D-Ser exerted the most potent therapeutic effect on IBD. Our findings revealed the impact of chirality on the colonic accumulation of the linear dipeptide, providing strategies for the colon-targeted delivery of the linear dipeptide for the treatment of IBD.