Objective To investigate the effects of ig administration and ip injection on the pharmacokinetic behavior and tissue distribution of tetrahydropalmatine (THP) in neuropathic pain model rats, and to evaluate the analgesic effects of the two administration routes against acute thermal pain in mice using the hot-plate test. Methods A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for determining THP concentrations in the plasma and tissues (including heart, liver, brain, lung, kidney) of neuropathic pain model rats. The pharmacokinetic parameters were fitted using the non-compartmental model with WinNonlin 7.0 software, and the distribution of THP in various rat tissues at different time points was investigated. Furthermore, the analgesic effects of THP via ig and ip routes in mice were explored, using the licking latency induced by warm thermal stimulation as the evaluation index. Results A quantitative method for determining THP was successfully established. The methodological validation results showed a good linear relationship (r = 0.999 3) between 0.5—1 250.0 ng/mL, the precision, accuracy and matrix effects all met the requirements of biological analysis. Pharmacokinetic results showed that compared with ig administration, ip administration led to faster absorption and higher bioavailability. The time to peak concentration (t_max) for the low-dose ip administration group (0.21 ±0.08) h was comparable to that of ig administration group (0.25 ±0.00) h, but its area under the plasma concentration-time curve (AUC_0—t) was significantly higher than that of ig administration group at 4 mg/kg dose. Regarding tissue distribution, THP was widely distributed in major rat tissues. At multiple time points, concentrations in the liver, kidney and other tissues, as well as plasma, were higher in ip administration group than in ig administration group. The liver and kidney were identified as the primary drug accumulation organs, and the brain tissue also showed relatively high exposure. Pharmacodynamics results indicated that both ig and ip administration significantly prolonged the licking latency in mice induced by warm thermal stimulation, with the ip administration group showing the best analgesic effect. Conclusion Compared to ig administration, ip administration offers advantages including faster absorption, higher bioavailability and more rapid tissue distribution. Both ig and ip administration routes exhibit significant analgesic effects, with ip administration showing the best efficacy. This verifies the consistency between pharmacodynamics and pharmacokinetics.

tetrahydropalmatine  /  ip administration  /  ig administration  /  pharmacokinetic behavior  /  tissue distribution  /  analgesic effect