@article {Masekdmd.110.037986, author = {Vlastimil Masek and Eva Anzenbacherova and Tomas Etrych and Jioi Strohalm and Karel Ulbrich and Pavel Anzenbacher}, title = {Interaction of HPMA copolymer-doxorubicin conjugates with human liver microsomal cytochromes P450. Comparison with free doxorubicin.}, elocation-id = {dmd.110.037986}, year = {2011}, doi = {10.1124/dmd.110.037986}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Interaction of nine forms of human hepatic cytochromes P450 (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) with two 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 N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers bearing doxorubicin attached to the polymeric carrier by A) hydrazone bond enabling intracellular pH-controlled drug release; or B) amide bond through enzymatically cleavable tetrapeptide GlyPheLeuGly spacer. Both polymeric conjugates differing in mechanism of their anti-tumor activity and the free doxorubicin as 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 (CYP) forms studied was negligible with 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 as well as their conjugates with DOX appear to be relatively safe at least in this respect, i.e. of inhibition of the liver microsomal drug metabolizing enzymes.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2011/06/03/dmd.110.037986}, eprint = {https://dmd.aspetjournals.org/content/early/2011/06/03/dmd.110.037986.full.pdf}, journal = {Drug Metabolism and Disposition} }