Bioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.
Bioavailability of penclomedine and systemic exposure to 4-O-demethylpenclomedine in patients receiving oral and intravenous penclomedine.
复制标题
接受口服和静脉注射喷氯米定的患者中喷氯米定的生物利用度和 4-O-去甲基喷氯米定的全身暴露。
DOI：
10.1007/s002800100346
复制
发表时间：
2001
影响因子：
3
通讯作者：
Strong,JM
中科院分区：
文献类型：
--
作者：
O'Reilly,S;Hartman,NR;Bowling,KM;Rowinsky,EK;Donehower,RC;Collins,J;Strong,JM
目的：基于临床前研究，研究了西洛梅定的口服给药，表明西洛梅定的口服治疗方案可以预防在静脉内（i. v.）方法：将喷克洛定以交替顺序静脉内（200 mg/m2）和口服（250 mg/m2）给药于恶性实体瘤患者。结果：所有患者口服盐酸喷氯美定后1 h内血浆中均可检测到喷氯美定，Cmax在1 ~ 4 h内达到。与口服给药方案可能避免神经毒性的假设一致，配对数据分析表明口服给药后Cmax值显著降低（P=0.017）。然而，这一减少的幅度变化很大。同样，观察到母体药物和代谢产物的相对暴露量范围很广。的生物利用度范围为28%至98%（中位数73%）。结论：口服阿克罗美定确实产生全身暴露，但大量的患者间的吸收和全身暴露的变异性是存在的，这可能会限制口服给药途径的临床作用。
Purpose:Oral administration of penclomedine was investigated based on preclinical studies indicating that an oral schedule of penclomedine treatment may prevent the neurotoxicity observed in phase I studies of an intravenous (i.v.) formulation, possibly by reducing maximum plasma concentrations (Cmax) of the neurotoxic parent species.Methods:Penclomedine was administered i.v. (200 mg/m2) and orally (250 mg/m2) in alternate sequences to patients with solid tumor malignancies. Plasma concentrations of parent drug and the principal metabolite, 4-O-demethylpenclomedine, were determined by a reversed-phase HPLC assay.Results:Penclomedine was detectable in the plasma of all patients within 1 h of oral penclomedine treatment and Cmaxwas reached within 1 to 4 h. Consistent with the hypothesis that an oral schedule of administration may circumvent neurotoxicity, a paired data analysis demonstrated a significant reduction in Cmaxvalues following oral administration (P=0.017). However the magnitude of this reduction was highly variable. Similarly an extensive range in the relative exposure to both parent drug and metabolite were observed. The bioavailability of penclomedine ranged from 28% to 98% (median 73%).Conclusions:Oral penclomedine does produce systemic exposure, but substantial interpatient variability in absorption and systemic exposure is present which may limit the clinical role of the oral route of administration.