Mudunuru Jennypher, Ren Chen, Taft David R, Maniar Manoj
Division of Pharmaceutical Sciences, Long Island University, 75 DeKalb Avenue, Brooklyn, NY, 11201, USA.
Onconova Therapeutics, Inc., Newtown, PA, USA.
Eur J Drug Metab Pharmacokinet. 2019 Aug;44(4):531-538. doi: 10.1007/s13318-019-00542-2.
ON 123300, a small molecule dual inhibitor of the c-MYC activated kinases ARK5 and CDK4/6, is being developed as a novel drug candidate for the treatment of cancer. The objective of this research was to evaluate gender differences in the in vitro metabolism and in vivo systemic exposure of ON 123300 in rats.
In vitro metabolism experiments (n = 2/group) were performed in rat liver microsomes from male and female donors. ON 123300 bislactate (final concentration 10 µM) was incubated with 0.5 mg/mL microsomes, and samples (100 µL) were withdrawn at specified incubation times over a period of 60 min, and immediately quenched and centrifuged. The supernatant was analyzed for ON 123300 and its metabolites by HPLC. ON 123300 (bislactate salt) pharmacokinetics were evaluated following intravenous (i.v.) (30 s infusion, 5 and 10 mg/kg) or oral administration (25 and 100 mg/kg) to male and female Sprague-Dawley rats (250-300 g). Following dosing, blood samples were collected over a time period up to 24 h. ON 123300 plasma concentrations were measured by LC-MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis. Plasma and microsomal binding of ON 123300 and blood:plasma ratio were also determined.
ON 123300 displayed more rapid microsomal degradation in vitro in males compared to females, as reflected in intrinsic clearance (181 vs 53.1 µL/min/mg). This translated into a significantly higher exposure of ON 123300 following oral administration to female rats, with the area under the curve (AUC) increasing nearly 3-fold (5617 ± 1914 ng·h/mL) compared to males (AUC = 1965 ± 749 ng·h/mL). This gender effect was less pronounced following i.v. dosing, where the AUC was ~ 2-fold higher in females. Based on these results, the higher plasma exposure observed in females can be primarily attributed to reductions in both hepatic clearance and presystemic metabolism compared to males.
This investigation demonstrated a significantly lower metabolism of ON 123300 in female rats, which resulted in high systemic exposure. Additional testing is warranted to assess the potential clinical implications of these findings.
ON 123300是一种c-MYC激活激酶ARK5和CDK4/6的小分子双重抑制剂，正作为一种新型抗癌候选药物进行研发。本研究的目的是评估ON 123300在大鼠体内的体外代谢和体内全身暴露的性别差异。
在来自雄性和雌性供体的大鼠肝微粒体中进行体外代谢实验（每组n = 2）。将ON 123300双乳酸盐（终浓度10 μM）与0.5 mg/mL微粒体一起孵育，在60分钟的时间段内于特定孵育时间抽取样品（100 μL），并立即淬灭和离心。通过高效液相色谱法分析上清液中的ON 123300及其代谢产物。对雄性和雌性Sprague-Dawley大鼠（250 - 300 g）静脉注射（30秒输注，5和10 mg/kg）或口服给药（25和100 mg/kg）后，评估ON 123300（双乳酸盐）的药代动力学。给药后，在长达24小时的时间段内采集血样。通过液相色谱 - 串联质谱法测量ON 123300的血浆浓度。通过非房室分析估算药代动力学参数。还测定了ON 123300的血浆和微粒体结合以及血药浓度比。
与雌性相比，ON 123300在雄性大鼠体外微粒体中的降解更快，这体现在内在清除率上（181对53.1 μL/min/mg）。这导致口服给药后雌性大鼠体内ON 123300的暴露显著更高，曲线下面积（AUC）比雄性增加了近3倍（5617±1914 ng·h/mL），而雄性的AUC为1965±749 ng·h/mL。静脉给药后这种性别效应不太明显，雌性的AUC仅高约2倍。基于这些结果，雌性中观察到的较高血浆暴露主要可归因于与雄性相比肝清除率和首过代谢的降低。
本研究表明雌性大鼠中ON 123300的代谢显著较低，这导致了较高的全身暴露。有必要进行进一步测试以评估这些发现的潜在临床意义。
