Pharmacokinetics Of Thienorphine And Its Metabolites

Thienorphine, a partial agonist and antagonist of the opioid receptor, had both antinociception and blocking morphine-induced antinociception activity and could persistently inhibited effects of morphine-induced dependence. Thienorphine had good application in treating addiction and was designed and synthesized by the institute of Pharmacology and Toxicology of AMMS. Thenorphine had multiple metabolic elimination and many metabolites was of pharmacologic activity. In this report, the pharmacology and Pharmacokinetics of thienorphine and thienorphine glucuronide metabolite had be investigated in rats, mice and dog. The research results reported as follows:1 The biotransformation of thienorphine was studies in rats after oral administration. The major metabolites were extracted by liquid-liquid extraction and solid phase extraction, isolated by thin-layer chromatography and identified by LC-MS/MS in faeces, urine and bile, (thienorphine glucuronides, thienorphine N-oxide, thienorphine oxysulfide, thiophenine) were and The biotransformation of thienorphine was involved in oxydation and N-dealkylation in phase I processes and glucuronosyl transferase in phase II metabolism.2 Thienorphine glucuronide, thienorphine N-oxide, thienorphine oxysulfide and thiophenine were chemical synthetized following result of transformation. In mice "hot plate" analgesia assay, comparison of analgesiarate induced by compounds, thiophenine was better, also thienorphine glucuronide and thienorphine N-oxide were the weaker than thienorphine. The concentration of thienorphine glucuronide was the larger, and thiophenine the smaller than thienorphine in the blood. Thienorphine and thiophenine were only monitored in rats brain.3 A simple, sensitive and selective method was developed to determine simultaneously the concentrations of thienorphine and its metabolite thienorphine glucuronide conjugate in rat plasma by LC-MS/MS analysis. The analytical procedure was applied as a routine analysis of biological samples to support a pharmacokinetic study.The concentration-time profiles of thienorphine and thienorphine glucuronide in blood followed an open two-compartment model with first-order absorption following a single oral administration of l,3,9mg/kg thienorphine to rats. Average peak concentrations for thienorphine were 2.32, 7.37, 14.21μg/L and the mean AUC were 11.95, 43.99, 105.24μg/L·h, respectively. The value of Tmax and the elimination half-life for thienorphine were a range from 2.2 to 3.0h and from 4.9 to 7.7h, respectively. The mean residence time for thienorphine were about 7h. The value of AUC and Average peak concentrations for thienorphine were linear with the administered dose, respectively. Average peak concentrations for thienorphine glucuronide were 35.13, 69.83, 284.63μg/L, respectively and the mean AUC were 142.17, 257.26, 1100.69μg/L·h, respectively. The value of Tmax , the elimination half-life and the mean residence time for thienorphine glucuronide were a range from 0.6 to 1.3h, from 4.4 to 7.2h and from 4.7to 5.5h, respectively. The value of AUC and Average peak concentrations for thienorphine glucuronide were also were linear with the administered dose, respectively. The results show that thienorphine glucuronide was more quickly absorbed and more quantitatively biotransformated than thienorphine. The absolute bioavailability of thienorphine to rats is about 9.66%.The concentration-time profiles of thienorphine and thienorphine glucuronide in blood followed an open two-compartment model with first-order absorption following a single oral administration of 0.2, 0.6, 1.8 mg/kg thienorphine to dogs. Average peak concentrations for thienorphine were 1.42, 2.08, 4.82μg/L, respectively and the mean AUC were 8.60, 13.24, 26.10μg/L·h, respectively. The value of Tmax , the elimination half-life and the mean residence time for thienorphine were a range from 0.55 to 0.65h, from 10 to 13h, from 10 to 12h, respectively. The value of AUC and Average peak concentrations for thienorphine were linear with the administered dose, respectively. Average peak concentrations for thienorphine glucuronide were 1.78, 5.03, 7.09μg/L, the mean AUC were 9.37, 22.34, 41.40μg/L·h, respectively. The value of Tmax , the elimination half-life and the mean residence time for thienorphine glucuronide were a range from 0.47 to 1.1 h, from 18 to 40h, from 11 to 17h. The value of AUC and Average peak concentrations for thienorphine glucuronide were linear with the administered dose, respectively. The pharmacokinetic parameters of thienorphine and thienorphine glucuronide following a single oral administration thienorphine to dogs were no difference respectively compared with the pharmacokinetic parameters after multiple oral administration had no difference. The way of multiple oral administration thienorphine to dogs did not lead to drug accumulation. The absolute bioavailability of thienorphine to dogs is about 12.65%.The tissue distribution and elimination of ³H-thienorphine were investigated in mice and rats by radioisotopic assay. The radioactivity in many organs was detected at 0.5 hour after single dosing orally (3mg/kg) to mice, and C_max was reached after 1h, but 1day in brain. The radioactivity eliminated slowly from body, small amounts of radioactivity was determinated at 8^th day. The radioactivity mainly eliminated by faeces excretion, and accumulate to 31.75% during 1 day, 63.81% during 2 day, 83.67% during 3day in faeces and urine following oral administration of 3 mg/kg thienorphine to rats. The radioactivity eliminated in bile was counted with 30% of total ³H-thienorphine.The value of plasma of rats and human bounding to ³H-thienorphine was about 95%. The same value among different species animal revealed no species differences, and no concentration relationship arrange from 10 to 800 ng/ml.4 The aim of autoradiography was to certificate the distribution of ³H-thienorphine binding in the tissue following oral ³H-thienorphine to mice. The density of silver grains overlying all tissue sections was small at 0.5 hour after single dosing orally, markedly increased at 1h. The density of silver grains overlying all tissue markedly reduced at 4^th day, otherwise, density of silver grains overlying CNS and gut were higher than others, because of the high binding affinities of thienorphine for opioid receptors the slow separation from opioid receptors in CNS and gut.