Acharya Milin R, Karp Judith E, Sausville Edward A, Hwang Kyunghwa, Ryan Qin, Gojo Ivana, Venitz Jurgen, Figg William D, Sparreboom Alex
Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD, USA.
Invest New Drugs. 2006 Sep;24(5):367-75. doi: 10.1007/s10637-005-5707-6.
To evaluate elimination pathways of the histone deacetylase inhibitor MS-275 in vitro and screen for relationships between demographic factors that may affect its pharmacokinetics in vivo.
Substrate specificity of MS-275 for the liver-specific organic anion transporting polypeptides (OATPs) was assessed using Xenopus laevis oocytes, and in vitro metabolism was evaluated using human liver microsomes. In vivo pharmacokinetic data were obtained from 64 adult patients (36 male/28 female; median age, 57 years) receiving MS-275 orally (dose range, 2 to 12 mg/m2).
Accumulation of [G-3H]MS-275 by oocytes expressing OATP1B1 or OATP1B3 was not significantly different from water-injected controls (p = 0.82). Furthermore, no metabolites could be detected after incubation of MS-275 in human liver microsomes, suggesting that hepatic metabolism is a minor pathway of elimination. The mean (+/- SD) apparent oral clearance of MS-275 was 38.5 +/- 18.7 L/h, with a coefficient of variation (%CV) of 48.7%. When clearance was adjusted for body-surface area (BSA), the inter-individual variability was similar (%CV = 50.1%). In addition, in a linear-regression analysis, except for adjusted ideal body weight (p = 0.02, |r| = 0.29), none of the studied measures (BSA, lean-body mass, ideal body weight, body-mass index, height, weight, age, and sex) was a significant covariate (p > 0.13; |r| < 0.11) for oral clearance.
The current analysis has eliminated a number of candidate covariates from further consideration as important determinants of MS-275 absorption and disposition. Furthermore, MS-275 can be added to the list of cancer drugs where BSA-based dosing is not more accurate than fixed dosing.
评估组蛋白脱乙酰酶抑制剂MS - 275的体外消除途径，并筛选可能影响其体内药代动力学的人口统计学因素之间的关系。
利用非洲爪蟾卵母细胞评估MS - 275对肝脏特异性有机阴离子转运多肽（OATPs）的底物特异性，并用人肝微粒体评估体外代谢。从64例口服MS - 275（剂量范围为2至12mg/m²）的成年患者（36例男性/28例女性；中位年龄57岁）获取体内药代动力学数据。
表达OATP1B1或OATP1B3的卵母细胞对[G - 3H]MS - 275的摄取与注射水的对照组无显著差异（p = 0.82）。此外，MS - 275与人肝微粒体孵育后未检测到代谢产物，提示肝脏代谢是次要的消除途径。MS - 275的平均（±标准差）表观口服清除率为38.5±18.7L/h，变异系数（%CV）为48.7%。当根据体表面积（BSA）调整清除率时，个体间变异性相似（%CV = 50.1%）。此外，在线性回归分析中，除了调整后的理想体重（p = 0.02，|r| = 0.29）外，所研究的指标（BSA、瘦体重、理想体重、体重指数、身高、体重、年龄和性别）均不是口服清除率的显著协变量（p > 0.13；|r| < 0.11）。
目前的分析排除了一些作为MS - 275吸收和处置重要决定因素的候选协变量，无需进一步考虑。此外，MS - 275可添加到基于体表面积给药并不比固定剂量给药更准确的癌症药物列表中。
