Pharmacokinetic Behavior of Tetrahydropalmatine via Different Administration Routes in a Rat Model of Neuropathic Pain and Its Analgesic Effect in Mice

• • Absolute bioavailability of THP at 4 mg/kg was 54.47% via ig versus >95.25% via ip, directly attributable to hepatic first-pass metabolism by CYP450; this 40.8 percentage-point improvement eliminates the gastrointestinal absorption barrier and substantially reduces required dose, a critical cost and efficacy consideration for clinical translation. • • ip administration achieved a tmax of 0.21 ± 0.08 h at 4 mg/kg, statistically comparable to ig (0.25 ± 0.00 h), but AUC0–t was significantly higher, indicating that despite similar absorption rates, ip avoids first-pass loss and yields greater systemic exposure; this supports ip as the preferred route for rapid analgesic onset in acute pain settings. • • In the hot-plate test, ip at 4 and 20 mg/kg significantly prolonged licking latency at 0.5 and 1.0 h (P < 0.05), whereas ig required 2 h (4 mg/kg) or 1 h (20 mg/kg) to reach significance (P < 0.05); the 0.5–1.0 h earlier onset for ip translates to faster therapeutic effect in acute thermal pain, a clinically meaningful advantage for emergency or breakthrough pain management. • • Tissue distribution revealed liver and kidney as primary enrichment organs, with ip yielding higher concentrations than ig at multiple time points; brain exposure was also notable, confirming central analgesic action. The absence of dose-dependent analgesia (no significant difference between 4 and 20 mg/kg) suggests receptor saturation or maximal effect at low dose, cautioning against dose escalation without pharmacokinetic monitoring.