title: Acyclic nucleoside phosphonates: a study on cytochrome P450 gene expression.
abstract: 1. Nucleotide analogues comprise an important class of drugs used in treatment of viral infections but also cancer. These drugs affect the structural integrity of DNA and activate different pathways and processes in the cell and may directly or indirectly influence the drug metabolizing system. Adefovir dipivoxil (AD) and tenofovir disoproxil (TD) are nucleotide analogues approved for the treatment of chronic hepatitis B and/or HIV/AIDS infection. 2. To evaluate the risk of their drug-drug interactions on the level of drug metabolism, an effect of both compounds on cytochromes P450 expression was studied using cDNA microarrays, real-time RT-PCR and immunoblotting. Mice were given intraperitoneally 25 mg/kg of AD or TD, respectively. As a positive control, a combination of prototypic cytochromes P450 (CYP) inducers, phenobarbital and β-naphthoflavone was chosen. 3. The data obtained showed a significant CYP induction in the positive control group, but no clinically significant induction of CYP genes by AD or TD was observed. Our results support the evidence of safety of AD and TD with respect to drug-drug interactions based on enzyme induction. These findings are important as a plethora of new antivirals of different types are being tested and introduced to clinical practice, mostly to be used in combinations.
authors.affiliation: Faculty of Medicine and Dentistry, Institute for Molecular and Translational Medicine, Palacky University , Olomouc , Czech Republic .
authors.forename: Jana
authors.initials: J
authors.lastname: Nekvindova
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Contreras
authors.forename: Peter
authors.initials: P
authors.lastname: Juvan
authors.forename: Klementina
authors.initials: K
authors.lastname: Fon Tacer
authors.forename: Pavel
authors.initials: P
authors.lastname: Anzenbacher
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Zidek
authors.forename: Michaela
authors.initials: M
authors.lastname: Kopecna Zapletalova
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.forename: Eva
authors.initials: E
authors.lastname: Anzenbacherova
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000068698:Tenofovir
chemical_list: D063065:Organophosphonates; D003577:Cytochrome P-450 Enzyme System; D000068698:Tenofovir; D000225:Adenine; C106812:adefovir dipivoxil
keywords: Adefovir; CYP; PMEA; PMPA; antiviral; drug metabolism; induction; tenofovir