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Relationships between Endogenous Plasma Biomarkers of Constitutive Cytochrome P 450 3 A Activity and Single‐Time‐Point Oral Midazolam Microdose Phenotype in Healthy Subjects
Author(s) -
Woolsey Sarah J.,
Beaton Melanie D.,
Choi YunHee,
Dresser George K.,
Gryn Steven E.,
Kim Richard B.,
Tirona Rommel G.
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12492
Subject(s) - microdose , cyp3a , midazolam , endogeny , pharmacology , pharmacokinetics , endocrinology , oral administration , basal (medicine) , chemistry , medicine , in vivo , cytochrome p450 , metabolism , biology , sedation , insulin , microbiology and biotechnology
Due to high basal interindividual variation in cytochrome P 450 3 A ( CYP 3 A ) 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 vivo CYP 3 A activity. The biomarkers 4β‐hydroxycholesterol (4β HC ) and 6β‐hydroxycortisol (6β HCL ) are sensitive to CYP 3 A induction and inhibition. However, their utility for the assessment of constitutive CYP 3 A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4β HC and 6β HCL ) are associated with basal CYP 3 A metabolic activity in healthy subjects assessed by a convenient single‐time‐point oral midazolam ( MDZ ) phenotyping strategy. Plasma 4β HC and 6β HCL metabolic ratios ( MR s) were analysed in 51 healthy adult participants. CYP 3 A activity was determined after administration of an oral MDZ microdose (100 μg). 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, 4β HC and 6β HCL MR s 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 4β HC MR ( p = 0.0003 and p = 0.032, respectively). Neither 4β HC nor 6β HCL MR s were associated with MDZ oral clearance. Plasma 4β HC and 6β HCL MR s do not relate to MDZ single‐time‐point metabolic phenotype in the assessment of constitutive CYP 3 A activity among healthy individuals.