Tone H, Iguchi H, Fujigaki M, Nishio M, Esumi Y, Takaichi M, Tsutsumi S, Yokoshima T
Jpn J Antibiot. 1986 Feb;39(2):612-28.
Blood levels, tissue distribution and excretion of (2''R)-4'-O-tetrahydropyranyladriamycin (THP) were studied in rats received 14C-THP or unlabeled THP at a dose of 5 mg/kg, respectively. The THP disappeared rapidly from the blood and transferred to tissues immediately after an administration. Pharmacokinetic analysis of the plasma level of THP by the simulation according to a three-compartment open model provided large values of apparent volume of distribution in the tissue compartment. The plasma half-lives of THP in alpha, beta and gamma-phases were 0.25 minute, 0.241 hour and 5.11 hours, respectively. The THP was distributed to the lung and spleen at a level about 100 times as high as the plasma level after an intravenous administration. A high level of THP was also found in the lymph node and gland tissues. Concentrations of THP in many tissues decreased to 1 microgram/g or less 24 or 72 hours after an injection of the drug, while the drug remained at higher levels in the thymus, spleen and tumor for a long time. After an injection of THP into the carotid artery, its distribution to the brain was apparent, but the level was lower after an injection to the tail vein. The amount of the drug transferred to a fetus was less than 0.2% of the dose. The major route for the excretion of THP after an intravenous administration was the fecal excretion via bile. Ratios of excretion of the radioactivity in the feces, urine and expired air were 80.3, 5.6 and 9.7% of the dose, respectively, 168 hours after an injection of 14C-THP. About 65% of the radioactivity was excreted in the bile up to 24 hours after injection but THP itself accounted for only 1/6 of the total radioactivity. About 80% of the excreted THP in the bile was in a conjugated form. Enterohepatic circulation of THP was observed mostly as metabolites or decomposed products of THP.
分别以5mg/kg的剂量给大鼠注射14C-吡柔比星（THP）或未标记的THP，研究了(2''R)-4'-O-四氢吡喃基阿霉素（THP）的血药浓度、组织分布及排泄情况。给药后，THP迅速从血液中消失并立即转移至组织中。根据三室开放模型进行模拟，对THP的血浆浓度进行药代动力学分析，结果显示组织室的表观分布容积值较大。THP在α、β和γ相的血浆半衰期分别为0.25分钟、0.241小时和5.11小时。静脉给药后，THP在肺和脾中的分布水平约为血浆水平的100倍。在淋巴结和腺体组织中也发现了高水平的THP。注射药物24或72小时后，许多组织中THP的浓度降至1μg/g或更低，而药物在胸腺、脾脏和肿瘤中长时间保持较高水平。将THP注入颈动脉后，其在脑中的分布明显，但尾静脉注射后水平较低。转移至胎儿体内的药物量不到给药剂量的0.2%。静脉给药后，THP的主要排泄途径是经胆汁的粪便排泄。注射14C-THP 168小时后，粪便、尿液和呼出气体中放射性的排泄比例分别为给药剂量的80.3%、5.6%和9.7%。注射后24小时内，约65%的放射性经胆汁排泄，但THP本身仅占总放射性的1/6。胆汁中排泄的THP约80%呈结合形式。THP的肠肝循环主要表现为THP的代谢产物或分解产物。
