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

INTRODUCTION: 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. METHODS: (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-ß-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). RESULTS: (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). CONCLUSIONS: 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.

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans.

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

7α,8α-Epoxynagilactones and their glucosides from the twigs of Podocarpus nagi: Isolation, structures, and cytotoxic activities.

A phytochemical investigation of twigs of Podocarpus nagi resulted in the identification of eight new type B nagilactones (1-8), all bearing a 7α,8α-epoxy-9(11)-enolide substructure, along with two known analogs (9-10). Their structures were determined on the basis of spectroscopic analysis, including HRESIMS, IR and NMR experiments, and X-ray crystallographic analysis. In vitro cytotoxic assay exhibited that compounds 1, 2, 9 and 10 could induce antiproliferation against three different types of human cancer cells while compounds 3 and 5 were inactive. Notably, the IC50 value of compound 1 is 0.208µM for A431 human epidermoid carcinoma cells, reaching the same level as the positive control combretastatin A-4 (0.104µM). Furthermore, compound 1 performed a strong inhibition of cancer cells by triggering apoptosis and arresting the cell cycle at G1 phase. These results unfold potential anticancer therapeutic applications of type B nagilactones.

Norditerpenoids and Dinorditerpenoids from the Seeds of Podocarpus nagi as Cytotoxic Agents and Autophagy Inducers.

Nine new norditerpenoids and dinorditerpenoids, 2-oxonagilactone A (1), 7ß-hydroxynagilactone D (2), nagilactones K and L (3 and 4), 3ß-hydroxynagilactone L (5), 2ß-hydroxynagilactone L (6), 3-epi-15-hydroxynagilactone D (7), 1α-chloro-2ß,3ß,15-trihydroxynagilactone L (8), and 15-hydroxynagilactone L (9), were isolated from the seeds of Podocarpus nagi, along with eight known analogues. The structures of the new compounds were established based on detailed NMR and HRESIMS analysis, as well as from their ECD spectra. The absolute configuration of the known compound 1-deoxy-2α-hydroxynagilactone A (16) was confirmed by single-crystal X-ray diffraction. All of the isolates were tested for their cytotoxic activities against cancer cells. The results indicated that compounds 4 and 6, as well as several known compounds, displayed cytotoxicity against A2780 and HEY cancer cells. Among the new compounds, 2ß-hydroxynagilactone L (6) showed IC50 values of less than 2.5 µM against the two cell lines used. Furthermore, compound 6 induced autophagic flux in A2780 cells, as evidenced by an enhanced expression level of the autophagy marker phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II) and increased mRFP-GFP-LC3 puncta. Also, compound 6 activated the c-Jun N-terminal kinase (JNK) pathway, while pretreatment with the JNK inhibitor SP600125 decreased compound 6-induced autophagy.

Novel Diterpenoids from the Twigs of Podocarpus nagi.

Phytochemical investigation of the twigs of Podocarpus nagi (Podocarpaceae) led to the isolation of two new abietane-type diterpenoids, named 1ß,16-dihydroxylambertic acid (1) and 3ß,16-dihydroxylambertic acid (2), along with two new ent-pimarane-type diterpenoids, named ent-2ß,15,16,18-tetrahydroxypimar-8(14)-ene (3) and ent-15-oxo-2ß,16,18-trihydroxypimar-8(14)-ene (4). Their respective structures were elucidated on the basis of spectroscopic analyses, including 1D- and 2D-NMR, IR, CD, and HR-ESI-MS. This is the first time ent-pimarane-type diterpenoids from the genus Podocarpus has been reported. All four new compounds were tested for cytotoxic activity. The MTT assay results showed that compounds 3 and 4 significantly inhibited the proliferation of human cervical cancer Hela cells, human lung cancer A549 cells, and human breast cancer MCF-7 cells at a concentration of 10 µM. Furthermore, using the lipopolysaccharide (LPS)-stimulated RAW264.7 cells, compounds 2 and 4 were found to significantly inhibit nitrogen oxide (NO) production with IC50 values of 26.5 ± 6.1 and 17.1 ± 1.5 µM, respectively.