Ipe, JosephLi, RudongMetzger, Ingrid F.Bo Li Lu, JessicaGufford, Brandon T.Desta, ZeruesenayLiu, YunlongSkaar, Todd C.2022-09-272022-09-272021-02Ipe, J., Li, R., Metzger, I. F., Bo Li Lu, J., Gufford, B. T., Desta, Z., Liu, Y., & Skaar, T. C. (2021). Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity. Clinical Pharmacology and Therapeutics, 109(2), 485–493. https://doi.org/10.1002/cpt.2018https://hdl.handle.net/1805/30135The CYP2B6 gene is highly polymorphic and its activity shows wide interindividual variability. However, substantial variability in CYP2B6 activity remains unexplained by the known CYP2B6 genetic variations. Circulating, cell-free micro RNAs (miRNAs) may serve as biomarkers of hepatic enzyme activity. CYP2B6 activity in 72 healthy volunteers was determined using the disposition of efavirenz as a probe drug. Circulating miRNA expression was quantified from baseline plasma samples. A linear model consisting of the effects of miRNA expression, genotype-determined metabolizer status, and demographic information was developed to predict CYP2B6 activity. Expression of 2,510 miRNAs were quantified out of which 7 miRNAs, together with the CYP2B6-genotypic metabolizer status and demographics, was shown to be predictive markers for CYP2B6 activity. The reproducibility of the model was evaluated by cross-validation. The average Pearson's correlation (R) between the predicted and observed maximum plasma concentration (C(max) ) ratios of efavirenz and its metabolite-8-OH efavirenz using the linear model with all features (7 miRNA + metabolizer status + age + sex + race) was 0.6702. Similar results were also observed using area under the curve (AUC) ratios (Pearson correlation's R = 0.6035). Thus, at least 36% (R(2) ) of the variability of in vivo CYP2B6 activity was explained using this model. This is a significant improvement over the models using only the genotype-based metabolizer status or the demographic information, which explained only 6% or less of the variability of in vivo CYP2B6 activity. Our results, therefore, demonstrate that circulating plasma miRNAs can be valuable biomarkers for in vivo CYP2B6 activity.enAdolescentAlkynes/therapeutic useAdultArticle