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.
- The American Society for Pharmacology and Experimental Therapeutics