title: Interaction of N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates with human liver microsomal cytochromes P450: comparison with free doxorubicin.
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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, CZ-775 15 Olomouc, Czech Republic. v.masek@gmail.com
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Masek
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherová
authors.forename: Tomás
authors.initials: T
authors.lastname: Etrych
authors.forename: Jirí
authors.initials: J
authors.lastname: Strohalm
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000737:chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000577:Amides; D065607:Cytochrome P-450 Enzyme Inhibitors; D003692:Delayed-Action Preparations; D006835:Hydrazones; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; C032976:N-(2-hydroxypropyl)methacrylamide