Abou El Hassan Mohamed A I, Kedde Marc A, Zwiers Ursula T H, Tourn E, Haenen Guido R M M, Bast Aalt, van der Vijgh Wim J F
Clinical Research Laboratory of Medical Oncology, Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Cancer Chemother Pharmacol. 2003 Nov;52(5):371-6. doi: 10.1007/s00280-003-0667-z. Epub 2003 Jul 31.
The pharmacokinetics and bioavailability of monoHER, a promising protector against doxorubicin-induced cardiotoxicity, were determined after different routes of administration.
Mice were treated with 500 mg.kg(-1) monoHER intraperitoneally (i.p.), subcutaneously (s.c.) or intravenously (i.v.) or with 1000 mg.kg(-1) orally. Heart tissue and plasma were collected 24 h after administration. In addition liver and kidney tissues were collected after s.c. administration. The levels of monoHER were measured by HPLC with electrochemical detection.
After i.v. administration the AUC(0-120 min) values of monoHER in plasma and heart tissue were 20.5+/-5.3 micromol.min.ml(-1) and 4.9+/-1.3 micromol.min.g(-1) wet tissue, respectively. After i.p. administration, a mean peak plasma concentration of about 130 microM monoHER was maintained from 5 to 15 min after administration. The AUC(0-120 min) values of monoHER were 6.1+/-1.1 micromol.min.ml(-1) and 1.6+/-0.4 micromol.min.g(-1) wet tissue in plasma and heart tissue, respectively. After s.c. administration, monoHER levels in plasma reached a maximum (about 230 microM) between 10 and 20 min after administration. The AUC(0-120 min) values of monoHER in plasma, heart, liver and kidney tissues were 8.0+/-0.6 micromol.min.ml(-1), 2.0+/-0.1, 22.4+/-2.0 and 20.5+/-5.7 micromol.min.g(-1), respectively. The i.p. and s.c. bioavailabilities were about 30% and 40%, respectively. After oral administration, monoHER could not be detected in plasma, indicating that monoHER had a very poor oral bioavailability.
MonoHER was amply taken up by the drug elimination organs liver and kidney and less by the target organ heart. Under cardioprotective conditions (500 mg/kg, i.p.), the Cmax was 131 microM and the AUC(infinity) was 6.3 microM.min. These values will be considered endpoints for the clinical phase I study of monoHER.
在不同给药途径后，测定有望预防阿霉素诱导的心脏毒性的单HER的药代动力学和生物利用度。
小鼠分别经腹腔内（i.p.）、皮下（s.c.）或静脉内（i.v.）给予500mg·kg⁻¹单HER，或经口服给予1000mg·kg⁻¹。给药后24小时收集心脏组织和血浆。此外，皮下给药后收集肝脏和肾脏组织。采用高效液相色谱电化学检测法测定单HER的水平。
静脉给药后，单HER在血浆和心脏组织中的AUC(0 - 120 min)值分别为20.5±5.3μmol·min·ml⁻¹和4.9±1.3μmol·min·g⁻¹湿组织。腹腔给药后，给药后5至15分钟维持单HER平均血浆峰浓度约130μM。单HER在血浆和心脏组织中的AUC(0 - 120 min)值分别为6.1±1.1μmol·min·ml⁻¹和1.6±0.4μmol·min·g⁻¹湿组织。皮下给药后，血浆中单HER水平在给药后10至20分钟达到最大值（约230μM）。单HER在血浆、心脏、肝脏和肾脏组织中的AUC(0 - 120 min)值分别为8.0±0.6μmol·min·ml⁻¹、2.0±0.1、22.4±2.0和20.5±5.7μmol·min·g⁻¹。腹腔和皮下生物利用度分别约为30%和40%。口服给药后，血浆中未检测到单HER，表明单HER口服生物利用度非常低。
单HER被药物清除器官肝脏和肾脏大量摄取，而被靶器官心脏摄取较少。在心脏保护条件下（500mg/kg，腹腔注射），Cmax为131μM且AUC(∞)为6.3μM·min。这些值将被视为单HER临床I期研究的终点。
