Drug enterohepatic circulation and disposition: constituents of systems pharmacokinetics

Gao, Yu; Shao, Jingwei; Zhou, Jiang; Chen, Jianzhong; Gu, Songen; Yu, Shasha; Zheng, Ke; Lee, Jia

doi:10.1016/j.drudis.2013.11.020

Cited by 51 publications

(40 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[ 15 ] The uniqueness of this compound lies on its long-lasting half-time in blood [ 16 ] due to, partially, its enterohepatic circulation as we analyzed by using systems pharmacokinetics. [ 17 ] The clinical trials of MIF, however, have not produced promising data to support its use as an anti-cancer drug, [ 14 ] probably because the postmetastatic chemotherapy is too late to impede CTCs from spreading to susceptible tissues. Nonetheless, because of its interruption of adhesion of colorectal cancer cells to endothelial cells, [ 18 ] its long-term use at clinics for psychotic depression which help cancer survivors cope with their psychological depression, as well as the above-mentioned pharmacological benefi ts, we therefore chose MIF as the metastasis chemopreventive agent with the hope that it can synergize aEpCAM in preventing CTCs from initiation of the metastatic cascade.…”

Section: The Circulating Tumor Cells (Ctcs) Existing In Cancer Survivmentioning

confidence: 99%

“…MIF is well-known about its long pharmacokinetic halflife as we summarized previously, [ 14,[16][17][18] we therefore used our established and well-validated method [ 16 ] and the MIF blood concentrations of mice in MSN-M or aE-MSN-M group was higher than that of MIF-treat group after 2 h (Figure 5 C). This phenomenon may collectively attribute to the slow and sustained-release of the entrapped MIF from MSN in vivo, and the intrinsic long half-life of MIF.…”

Section: In Vivo Metastasis Prevention Effi Cacy and Related Pharmacomentioning

confidence: 99%

See 1 more Smart Citation

The Architecture and Function of Monoclonal Antibody‐Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention

Gao

Zhang

et al. 2016

Small

Self Cite

View full text Add to dashboard Cite

The circulating tumor cells (CTCs) existing in cancer survivors are considered the root cause of cancer metastasis. To prevent the devastating metastasis cascade from initiation, we hypothesize that a biodegradable nanomaterial loaded with the abortifacient mifepristone (MIF) and conjugated with the epithelial cell adhesion molecule antibody (aEpCAM) may serve as a safe and effective cancer metastatic preventive agent by targeting CTCs and preventing their adhesion-invasion to vascular intima. It is demonstrated that MIF-loaded mesoporous silica nanoparticles (MSN) coated with aEpCAM (aE-MSN-M) can specifically target and bind colorectal cancer cells in either cell medium or blood through EpCAM recognition proven by quantitative flow cytometric detection and free aEpCAM competitive assay. The specific binding results in downregulation of the captured cells and drives them into G0/G1 phase primarily attributed to the effect of aEpCAM. The functional nanoparticles significantly inhibit the heteroadhesion between cancer cells and endothelial cells, suggesting the combined inhibition effects of aEpCAM and MIF on E-selectin and ICAM-1 expression. The functionalized nanoparticles circulate in mouse blood long enough to deliver MIF and inhibit lung metastasis. The present proof-of-concept study shows that the aE-MSN-M can prevent cancer metastasis by restraining CTC activity and their adhesion-invasion to vascular intima.

show abstract

Section: The Circulating Tumor Cells (Ctcs) Existing In Cancer Survivmentioning

confidence: 99%

Section: In Vivo Metastasis Prevention Effi Cacy and Related Pharmacomentioning

confidence: 99%

The Architecture and Function of Monoclonal Antibody‐Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention

Gao

Zhang

et al. 2016

Small

Self Cite

View full text Add to dashboard Cite

show abstract

“…We showed that mifepristone possesses the unique property of enterohepatic circulation 22 , and high plasma protein binding rate at 90% 23 . The enterohepatic recycling could prolong the half-life of the recycled drug like metapristone.…”

Section: Discussionmentioning

confidence: 88%

Sex-related pharmacokinetic differences and mechanisms of metapristone (RU486 metabolite)

Chen

Xiao

Chen

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Metapristone is the primary metabolite of the abortifacient mifepristone (RU486), and is being developed as a safe and effective cancer metastatic chemopreventive agent for both sexes. Here, we systematically investigated the sex-related pharmacokinetics of metapristone in both rats and dogs, and explored the related mechanisms of actions. Administration of metapristone to rats and dogs showed that plasma concentrations of metapristone (AUC, C max) were significantly higher in female dogs and rats than in males. The sex-related differences in pharmacokinetics become more significant after ten consecutive days of oral administration. Female liver microsomes metabolized metapristone significantly slower than the male ones. The results from P450 reaction phenotyping using recombinant cDNA-expressed human CYPs in conjunction with specific CYP inhibitors suggested that CYP1A2 and CYP3A4 are the predominant CYPs involved in the metapristone metabolism, which were further confirmed by the enhanced protein levels of CYP1A2 and CYP3A4 induced by 1-week oral administration of metapristone to rats. The highest tissue concentration of metapristone was found in the liver. The study demonstrates, for the first time, the sex-related pharmacokinetics of metapristone, and reveals that activities of liver microsomal CYP1A2 and CYP3A4 as well as the renal clearance are primarily responsible for the sex-related pharmacokinetics.

show abstract

“…These effects are similar to those previously reported for ABZ, which suggests that compound 3 shares the same mechanism of action. 31,32) Pharmacokinetic Study Figure 5 shows the pharmacokinetic profile of compound 3 after an oral administration. The sensitivity of the method allowed us to quantify plasma concentrations up to 30 h post-dose.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of New Benzimidazole Derivatives as Cysticidal Agents: <i>In Vitro</i>, <i>in Vivo</i> and Docking Studies

González-Hernández

Palomares-Alonso

Becerril-Vega

et al. 2019

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Based on our previous research on cysticidal drugs, we report the synthesis and evaluation of three new benzimidazole derivatives. In these compounds, the amido group was used as a bioisosteric replacement of the ester group. The molecular docking on β-tubulin revealed that the derivatives interacted through hydrogen bonding with N165, E198 and V236. All compounds showed in vitro activity against Taenia crassiceps cysts. Among them, benzimidazole 3 was found to be the most potent of the series (EC 50 0.86 µM). This compound also exhibited the highest probability of binding and the lowest binding free energy score and was therefore selected for in vivo evaluation. Results indicated that the efficacy of compound 3 was comparable to that of the reference drug, albendazole (50.39 vs. 47.16% parasite reduction). Animals treated with compound 3 seemed to tolerate this benzimidazole well, with no changes in behavior, or food and water consumption. These findings are consistent with the in silico prediction results, which indicated low toxicity risks. The pharmacokinetic study showed that the half-life and mean residence time (6.06 and 11.9 h, respectively) were long after oral administration. Together, these results indicate that this new benzimidazole derivative represents a promising structure with cysticidal activity.

show abstract

Drug enterohepatic circulation and disposition: constituents of systems pharmacokinetics

Cited by 51 publications

References 68 publications

The Architecture and Function of Monoclonal Antibody‐Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention

The Architecture and Function of Monoclonal Antibody‐Functionalized Mesoporous Silica Nanoparticles Loaded with Mifepristone: Repurposing Abortifacient for Cancer Metastatic Chemoprevention

Sex-related pharmacokinetic differences and mechanisms of metapristone (RU486 metabolite)

Evaluation of New Benzimidazole Derivatives as Cysticidal Agents: <i>In Vitro</i>, <i>in Vivo</i> and Docking Studies

Contact Info

Product

Resources

About