Workman P, White R A, Walton M I, Owen L N, Twentyman P R
Br J Cancer. 1984 Sep;50(3):291-303. doi: 10.1038/bjc.1984.176.
Benznidazole is a lipophilic analogue of misonidazole (MISO) which shows promise as a chemosensitizer for clinical use, particularly in combination with CCNU. We have investigated the detailed pharmacokinetics of benznidazole in mice, dogs and sheep to provide a data base for the estimation of doses required for chemosensitization in man. Pharmacokinetic behaviour was linear except at high doses in mice. Absorption was fairly rapid and bioavailability was complete following both i.p. administration in mice and oral administration in dogs. Elimination t1/2 values were longer than for MISO, being 90 min in mice, 4-5 h in sheep and 9-11 h in dogs. At doses giving linear kinetics, peak whole plasma concentrations per administered mg kg-1 were 0.75 micrograms ml-1 for the i.p. route in mice and 1.8 micrograms ml-1 for the oral route in dogs. Though between 39 and 59% of plasma benznidazole was bound to protein, tissue penetration was generally good. Tissue/whole plasma ratios ranged from 59-99% for transplantable mouse tumours and from 14-70% for spontaneous dog neoplasms. Nervous tissue penetration was similar to that in tumours: brain/whole plasma ratios averaged between 61 and 76% in mice and 42% in dogs, while peripheral nerve/whole plasma ratios in dogs averaged 74%. Mean liver/whole plasma ratios were 42% and 71% in BALB/c and C3H/He mouse strains respectively. Only approximately 5% of the administered dose was excreted unchanged in the urine, indicating the likelihood of extensive metabolism. These data show that benznidazole should have suitable pharmacokinetic properties for clinical use as a chemosensitizer. Enhancement of CCNU response is likely to require circulating benznidazole concentrations of 10-30 micrograms ml-1 and we predict that these will be obtained with oral doses of 6-20 mg kg-1 in man.
苯硝唑是米索硝唑（MISO）的亲脂性类似物，作为一种临床用化学增敏剂显示出应用前景，特别是与洛莫司汀联合使用时。我们研究了苯硝唑在小鼠、狗和绵羊体内的详细药代动力学，以提供估算人体化学增敏所需剂量的数据库。除了在小鼠高剂量时，药代动力学行为呈线性。吸收相当迅速，在小鼠腹腔注射和狗口服给药后生物利用度均为完全。消除半衰期值比米索硝唑长，小鼠为90分钟，绵羊为4 - 5小时，狗为9 - 11小时。在呈线性动力学的剂量下，每毫克千克给药量的全血药峰浓度，小鼠腹腔注射途径为0.75微克/毫升，狗口服途径为1.8微克/毫升。虽然血浆中39%至59%的苯硝唑与蛋白质结合，但组织穿透性总体良好。可移植小鼠肿瘤的组织/全血药浓度比范围为59% - 99%，自发狗肿瘤的该比值范围为14% - 70%。神经组织的穿透性与肿瘤相似：小鼠脑/全血药浓度比平均在61%至76%之间，狗为42%，而狗外周神经/全血药浓度比平均为74%。BALB/c和C3H/He小鼠品系的肝/全血药浓度比分别为42%和71%。给药剂量中只有约5%以原形经尿液排泄，表明可能存在广泛代谢。这些数据表明苯硝唑作为化学增敏剂临床应用时应具有合适的药代动力学特性。增强洛莫司汀反应可能需要循环苯硝唑浓度达到10 - 30微克/毫升，我们预测人体口服6 - 20毫克/千克剂量可达到这一浓度。
