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Effects of MicroRNA‐34a on the Pharmacokinetics of Cytochrome P450 Probe Drugs in Mice
Author(s) -
Jilek Joseph Lionel,
Tian Ye,
Yu AiMing
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.822.8
Subject(s) - chlorzoxazone , pharmacology , dextromethorphan , phenacetin , pharmacokinetics , diclofenac , midazolam , chemistry , drug interaction , pregnenolone , cytochrome p450 , cyp2e1 , medicine , enzyme , biochemistry , hormone , steroid , sedation
MicroRNAs (miR) including miR‐34a have been shown to regulate nuclear receptor, drug‐metabolizing enzyme and transporter gene expression in cell models. However, the degree to which miRNAs affect pharmacokinetics (PK) at the systemic level remains unknown. Additionally, miR‐34a replacement therapy represents a new cancer treatment strategy, however it is undefined if miR‐34a therapeutics elicit any drug‐drug interactions (DDI). To address these questions, we developed a practical single‐mouse PK approach and investigated the effects of a bioengineered miR‐34a prodrug on the PK of five cytochrome P450 (CYP) probe substrates (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail to mouse models. This approach utilized manual serial blood microsampling from a single mouse and a sensitive LC‐MS/MS assay. This approach was validated by the sharp changes in midazolam PK by ketoconazole and pregnenolone 16α‐carbonitrile as well as phenacetin PK by a‐napthoflavone and 3‐methylcholanthrene. Surprisingly, 3‐methylcholanthrene also decreased systemic exposure to midazolam, while both pregnenolone 16a‐carbonitrile and 3‐methylcholanthrene largely reduced the exposure to dextromethorphan, diclofenac and chlorzoxazone. Finally, miR‐34a 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 the single‐mouse PK model suggest that therapeutic miR‐34a might have minor or no effects on the PK of CYP‐metabolized drugs co‐administered. Support or Funding Information This study was supported by grants [R01GM133888] and [U01CA175315] from NIH. J.L.J. was supported by a NIGMS Pharmacology Training Program [T32GM099608].