Pharmacokinetics And Distribution Of Huwentoxin-Ⅰafter Epidural And Intravenous Administration To Rats And Rhesus Monkeys

Huwentoxin-I (HWTX-I) is a peptide neurotoxin (with amino acid sequence of ACKGV FDACT PGKNE CCPNR VCSDK HKWCK WKL) isolated and purified from the venom of the Chinese bird spider {Selenocosmia huwena) .We studied and compared pharmacokinetics (PK) and distribution after epidural or iv administration of (125)^I-labelled Huwentoxin-I ((125)^I-HWTX-I) in rats. HWTX-I was labeled by iodogen method. Single dose of 2.6, 1.7, or 0.86 MBq/kg (125)^I-HWTX-I per rat (about 25, 50, 75 μg/kg) were injected via a catheter implanted in epidural space or iv at high dose. Serum (125)^I-HWTX-I was determined by reverse phase high liquid chromagraphy with flow scintillation detector. Radioactivity detected in dural-vertebral samples was (22 ?8) % of injected radioactivity at 10 min after epidural injection, which demonstrated successful administration into epidural space. Concentration-time curves of (125)^I-HWTX-I after two routes were different. Absorption phase with C_max, at 10 min was observed after epidural. (125)^I-degradation products at 10 min after epidural and iv injection of high dose were (2. 1 ?1. 1) and (6. 8 ?2. 5) ng eqv/mL, respectively (P < 0. 01). C_max and AUC were increased with dose after epidural administration. Terminal T_1/2 after epidural or iv administration were 2. 5, 2. 8 h or 2. 3 h, respectively. Cl was 0. 74 and 1. 18L/h/kg after both routes. Bioavailability after epidural administration was > 90 %. Excretion of radioactivity was mainly via urine. The differences between vertebral of HWTX-I, as well as degradation profiles after epidural and iv injection supported the using of HWTX-I as an algesic by epidural administration.Radioactivity in dural-vertebral samples was significantly higher after ed than those after iv at 2 h after administration,indicating a successful injection of (125)^I-Huwentoxin-I into epidural-space.Radioactivity in epidural space declined post injection and sustained for a long time after ed injection. Radioactivity showed a gradient in body tissues after ed injection. The distribution profiles after iv were similar to ed but 3-4 fold higher in most tissues at 10 min. The highest concentrations in most tissues were found at 2 h after ed injection and at 10 min after iv. The bio-distribution profiles after epidural and iv injection confirmed the high concentration in dural-vertebral samples, which is coincided with the analgesic activity observed after epidural injection and not after intravenously.We also studied and compared pharmacokinetics (PK) and distribution after epidural or intravenous (iv) administration of (125)^I-labeled Huwentoxin-I ((125)^I-Huwentoxin-I) in rhesus monkeys. Huwentoxin-1 was labeled by iodogen method and was administered at a dose of 0. 388 MBq/kg (about 11. 2ug/kg) by lumbar puncture at the third lumbar (L3) and the forth lumbar (L4) interspaces using a 12-gauge paracentetic needle into epidural space of rhesus monkeys or iv at the same dose. Reverse-Phase High Performance Liquid Chromatography (RHPLC) determined serum (125)^I-Huwentoxin-I with an automatic gamma counter. The puriation of (125)^I-Huwentoxin-I >96 % and with the same bio-activity as unlabeled Huwentoxin-1; Radioactivity detected in epidural space was 38 % of injected radioactivity at 10 min after epidural injection, which demonstrated successful administration into epidural space; The maximum serum concentration after epidural or iv administration of (125)^I-labeled Huwentoxin-I were determined to be (19. 1?. 8)ng equ/mL and (119. 4?3. 0)ng equ/mL (P<0.01), respectively, at the maximum serum concentration times of 30 min and 2 min. Terminal Tl/2 after epidural or ivadministration were(15. 1+1. 8)h or(15. 0+2. l)h, respectively. Cl was (0. 066+0. 004) L/h/kg or (0. 064+0. 012) L/h/kg, respectively. Bioavailability after epidural administration was > 94 %. Concentration-time curves of (125)^l-labeled Huwentoxin-1 after two routes were different. The degradation profiles after epidural and iv injection supported the using of HWTX-I as analge...