Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P450 3A Activity and Single-Time-Point Oral Midazolam Microdose Phenotype in Healthy Subjects

Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug phenotyping strategies, as well as endogenous biomarkers for assessment of in vivoCYP3A activity. The biomarkers 4-hydroxycholesterol (4HC) and 6-hydroxycortisol (6HCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4HC and 6HCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single-time-point oral midazolam (MDZ) phenotyping strategy. Plasma 4HC and 6HCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 g). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4HC and 6HCL MRs ranged 6.5-, 10- and 13-fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4HC MR (p = 0.0003 and p = 0.032, respectively). Neither 4HC nor 6HCL MRs were associated with MDZ oral clearance. Plasma 4HC and 6HCL MRs do not relate to MDZ single-time-point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.