Circulating miRNAs as Biomarkers for CYP2B6 Enzyme Activity.
Clin Pharmacol Ther
; 109(2): 485-493, 2021 02.
Article
in En
| MEDLINE
| ID: mdl-32772362
The 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 (Cmax ) 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% (R2 ) 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biomarkers
/
MicroRNAs
/
Cytochrome P-450 CYP2B6
Type of study:
Prognostic_studies
Limits:
Adolescent
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Adult
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Clin Pharmacol Ther
Year:
2021
Document type:
Article
Affiliation country:
United States
Country of publication:
United States