Herb-Drug Interaction of Total Glucosides of Paeony and Tripterygium Glycoside with Celecoxib in Beagle Dogs by UPLC-MS/MS.

Abstract

Background and objective: Total glucosides of paeony (TGP) capsules, tripterygium glycoside tablets (TGT), and celecoxib are commonly used drugs in clinical practice for the treatment of Rheumatoid arthritis (RA). An UPLC-MS/MS method for the analysis of celecoxib in beagle dogs was developed, the herb-drug interactions (HDIs) between TGP and TGT with celecoxib were studied based on pharmacokinetics.

Methods: The method of acetonitrile precipitation was applied to process plasma samples. Celecoxib and furosemide (internal standard, IS) was separated by gradient elution, and detected using multiple reaction monitoring mode under the positive ion. The ion reactions used for quantitative analysis were m/z 379.82 → 315.82 for celecoxib, and m/z 328.74 → 204.88 for IS. HDIs experiments adopt a three-stage experimental design. In the first period, six beagle dogs was orally administered 6.67 mg/kg celecoxib. In the second period, TGP 20 mg/kg was given orally twice a day for 7 consecutive days, then celecoxib was orally administered. And, in the third period, TGT 1.5 mg/kg was orally given, twice a day for 7 consecutive days, then celecoxib was orally administered. The concentration of celecoxib in the three periods was detected, and HDIs were evaluated based on pharmacokinetics.

Results: Celecoxib exhibited good linearity in the range of 10-2000 ng/mL. The accuracy, precision, recoveries, matrix effects, and stability all met the standards. When celecoxib was used in combination with TGPC or TGT, the main pharmacokinetic parameters of celecoxib changed, C_max, AUC_(0-t) and AUC_(0-∞) increased, t_½ was prolonged, and CL and V_d decreased.

Conclusion: A novel UPLC-MS/MS approach was successfully performed and applied to measure celecoxib in beagle dog plasma. TGP and TGT could inhibit the metabolism of celecoxib in beagle dogs, thereby affecting the pharmacokinetic parameters of celecoxib and increasing plasma exposure to celecoxib.