Pharmacokinetic Behavior of Tetrahydropalmatine via Different Administration Routes in a Rat Model of Neuropathic Pain and Its Analgesic Effect in Mice
This study systematically compared the pharmacokinetic behavior and tissue distribution of tetrahydropalmatine (THP) following intragastric (ig) and intraperitoneal (ip) administration in a rat model of neuropathic pain, and evaluated analgesic efficacy against acute thermal pain in mice using the hot-plate test. A rapid, sensitive LC-MS/MS method was validated for THP quantification in plasma and tissues (heart, liver, brain, lung, kidney), with linearity from 0.5 to 1250.0 ng/mL (r = 0.9993) and acceptable precision, accuracy, and matrix effects. Non-compartmental analysis using WinNonlin 7.0 revealed that ip administration achieved faster absorption and higher bioavailability than ig. At 4 mg/kg, ip administration yielded a tmax of 0.21 ± 0.08 h, comparable to ig (0.25 ± 0.00 h), but significantly greater AUC0–t. Tissue distribution showed widespread THP exposure, with ip producing higher concentrations in liver, kidney, and plasma at multiple time points; liver and kidney were primary enrichment organs, with notable brain exposure. In the hot-plate test, both routes significantly prolonged licking latency, but ip administration produced superior analgesia. At 4 and 20 mg/kg, ip significantly increased 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 achieve significance (P < 0.05), indicating faster onset for ip. The study confirms that ip administration offers faster absorption, higher bioavailability, and more rapid tissue distribution, with pharmacodynamic responses consistent with pharmacokinetic exposure. These findings provide a pharmacokinetic and pharmacodynamic basis for clinical route selection and dose optimization of THP.