Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats

Publication: Cancer Chemother Pharmacol
Software: GastroPlus®
Division: Simulations Plus


Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood–brain barrier (BBB) is unknown.

(1) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-β-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study).

(1) Rapid drug elimination was observed 24 h after intragastric administration. The total cumulative excretion in urine and feces within 168 h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72 h. The drug-related substances were extensively distributed to the tissues within 48 h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The Kp,uu,brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01).

CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.

By Xin-mei Li, Yuan-dong Zheng, Yi-fan Zhang, Xia-juan Huan, Chen Yang, Meng-ling Liu, Xiao-kun Shen, Chun-hao Yang & Xing-xing Diao