The effect of multidrug resistance modulator HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in xenograft-nude mice.

Abstract

To overcome MDR (multidrug resistance) of cancer mediated by P-gp (P-glycoprotein) has become a key strategy to improve the survival rate in clinic. Therefore, it is imperative to develop advanced modulators that have no side effects or interactions with cytotoxic drugs. HZ08, which acts as a P-gp inhibitor, shows a notable reverse effect with low cytotoxicity in vitro. Based on the previous results, the goal of this experiment is to elucidate the effect of HZ08 on pharmacodynamics and pharmacokinetics of adriamycin in tumor-bearing nude mice. Several criterions and methods, such as tumor weight and volume, in vivo imaging, western blot, immunohistochemistry as well as ATPase hydrolysis assay were selected to evaluate the reversing activity and mechanism of HZ08 on MDR; Furthermore, fluorescence detection assay was applied to determine the distribution of adriamycin in the blood and tissues. This study revealed that HZ08 potentiated the anti-tumor activity of adriamycin but with little effect on the expression of P-gp in vivo. Adriamycin accumulation in tumor was enhanced by HZ08 via ATPase activity inhibition. In addition, HZ08 did not alter the pharmacokinetic characteristic of adriamycin in plasma or tissues. In conclusion, HZ08 showed dramatic MDR reversing activity and had no influence on the pharmacokinetics of adriamycin.

• Authors: Yanyan Zhang, Yidong Feng, Kodithuwakku Nandani Darshika, Bo Zhang, Yahui Hu, Weirong Fang, Yunman Li, Wenlong Huang
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 66 Pg. 109-17 (Jan 23 2015) ISSN: 1879-0720 [Electronic] Netherlands
• PMID: 25459530 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• Isoquinolines
• N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide
• Doxorubicin
• Adenosine Triphosphatases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Adenosine Triphosphatases (metabolism)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Area Under Curve
• Cell Line, Tumor
• Doxorubicin (administration & dosage, pharmacokinetics, therapeutic use)
• Drug Resistance, Neoplasm
• Gene Expression Regulation (drug effects)
• Half-Life
• Isoquinolines (administration & dosage, chemistry, pharmacology)
• Mice
• Mice, Nude
• Molecular Structure
• Neoplasms, Experimental (drug therapy)
• Tissue Distribution