RT Journal Article
SR Electronic
T1 Effects of MicroRNA-34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.116.074344
DO 10.1124/dmd.116.074344
A1 Joseph L. Jilek
A1 Ye Tian
A1 Ai-Ming Yu
YR 2017
UL http://dmd.aspetjournals.org/content/early/2017/03/02/dmd.116.074344.abstract
AB MicroRNAs (miR) 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 would affect pharmacokinetics (PK) at the systemic level remains unknown. Additionally, miR-34a replacement therapy represents a new cancer treatment strategy, whereas it is undefined if miR-34a therapeutics would causes any drug-drug interactions (DDI). To address the questions, we developed a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of multiple Cytochrome P450 (CYP) probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail to mouse models. This approach involves manual serial blood microsampling from a single mouse and requires a sensitive LC-MS/MS assay, which was able to illustrate the sharp changes in midazolam PK by ketoconazole and pregnenolone 16α-carbonitrile as well as phenacetin PK by α-napthoflavone and 3-methylcholanthrene. Surprisingly, 3-methylcholanthrene also decreased systemic exposure to midazolam, while 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 dextromethorphan, phenacetin and chlorzoxazone, and caused a marginal (45-48%) increase in systemic exposure to midazolam and diclofenac in mice. These findings from single-mouse PK model suggest that miR-34a might have minor or no effects on the PK of CYP-metabolized drugs co-administered.