title: Effects of MicroRNA-34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice.
abstract: MicroRNAs (miRNAs or miRs), including miR-34a, have been shown to regulate nuclear receptor, drug-metabolizing enzyme, and transporter gene expression in various cell model systems. However, to what degree miRNAs affect pharmacokinetics (PK) at the systemic level remains unknown. In addition, miR-34a replacement therapy represents a new cancer treatment strategy, although it is unknown whether miR-34a therapeutic agents could elicit any drug-drug interactions. To address this question, we refined a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of several cytochrome P450 probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail. This approach involves manual serial blood microsampling from a single mouse and requires a sensitive liquid chromatography-tandem mass spectrometry assay, which was able to illustrate the sharp changes in midazolam PK by ketoconazole and pregnenolone 16α-carbonitrile as well as phenacetin PK byα-naphthoflavone and 3-methylcholanthrene. Surprisingly, 3-methylcholanthrene also decreased systemic exposure to midazolam, whereas both pregnenolone 16α-carbonitrile and 3-methylcholanthrene largely reduced the exposure to dextromethorphan, diclofenac, and chlorzoxazone. Finally, the biologic miR-34a agent had no significant effects on the PK of cocktail drugs but caused a marginal (45%-48%) increase in systemic exposure to midazolam, phenacetin, and dextromethorphan in mice. In vitro validation of these data suggested that miR-34a slightly attenuated intrinsic clearance of dextromethorphan. These findings from single-mouse PK and corresponding mouse liver microsome models suggest that miR-34a might have minor or no effects on the PK of coadministered cytochrome P450-metabolized drugs.
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California (J.L.J., Y.T., A.-M.Y.); and Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China (Y.T.).
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Jilek
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California (J.L.J., Y.T., A.-M.Y.); and Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China (Y.T.).
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California (J.L.J., Y.T., A.-M.Y.); and Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China (Y.T.) aimyu@ucdavis.edu.
authors.forename: Ai-Ming
authors.initials: AM
authors.lastname: Yu
mesh_terms: D000818:Animals; D002753:Chlorzoxazone / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D004008:Diclofenac / Q000493:pharmacokinetics; D004347:Drug Interactions; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000494:pharmacology*; D008874:Midazolam / Q000493:pharmacokinetics; D010599:Pharmacokinetics; D010615:Phenacetin / Q000493:pharmacokinetics
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D004008:Diclofenac; D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D010615:Phenacetin; D002753:Chlorzoxazone; D008874:Midazolam