Abstract
Interaction of nine forms of human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) with two N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based doxorubicin (DOX) conjugates designed for passive tumor targeting was studied using pooled human microsomes. The compounds used in this study were two high-molecular-weight HPMA copolymers bearing doxorubicin attached to the polymeric carrier by 1) hydrazone bond enabling intracellular pH-controlled drug release or 2) amide bond through enzymatically cleavable tetrapeptide GlyPheLeuGly spacer. Both polymeric conjugates differing in mechanism of their antitumor activity and the free doxorubicin as the control were tested for potential inhibition activity. Among nine cytochrome P450 forms studied, no HPMA copolymer with bound DOX caused an inhibition of potential clinical significance. The extent of inhibition of enzymatic activities of the cytochrome P450 forms studied was negligible with the exception of CYP2B6 and was apparently caused by DOX as no inhibition was observed with polymers alone, and the extent of inhibition by the complex corresponded to this of the free DOX at the same concentration. In conclusion, the polymers and their conjugates with DOX seem to be relatively safe, at least in this respect, i.e., of inhibition of the liver microsomal drug-metabolizing enzymes.
Footnotes
This work was supported by the Czech Academy of Sciences [Grant KAN 200200651]; and the Ministry of Education of Czech Republic [Grant MSM 6198959216]. The infrastructural part of this project (Institute of Molecular and Translational Medicine) was supported by the Operational Programme Research and Development for Innovations [Project CZ.1.05/2.1.00/01.0030].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037986.
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ABBREVIATIONS:
- P450
- cytochrome P450
- HPMA
- N-(2-hydroxypropyl)methacrylamide
- DOX
- doxorubicin
- DOX·HCl
- doxorubicin hydrochloride
- AIBN
- 2,2′-azobis(isobutyronitrile)
- DMSO
- dimethyl sulfoxide
- AP
- 1-aminopropan-2-ol.
- Received January 6, 2011.
- Accepted June 3, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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