title: Does the long plasma half-life of 4beta-hydroxycholesterol impact its utility as a cytochrome P450 3A (CYP3A) metric?
abstract: Plasma 4β-hydroxycholesterol (4βHC) has been proposed as an endogenous marker of cytochrome P450 3A (CYP3A). To assess its utility as a CYP3A metric, a pharmacokinetic model, assuming no alteration in cholesterol plasma concentrations, was developed to simulate the effect of CYP3A induction and inhibition on 4βHC plasma levels under different treatment durations. By incorporating the long plasma half-life of 4βHC (~17 days) into the model, the inductive effect of 2 known inducers (carbamazepine and rifampicin) reported in the literature was adequately described. Furthermore, the simulations showed that it was possible to resolve none, weak, moderate, and potent inducers within 2 weeks of dosing. On the other hand, simulations indicated that at least 2 weeks of dosing would be needed to detect the potent inhibition of CYP3A (maximal ~40% decrease in 4βHC plasma levels). Greater differentiation of weak, moderate, and potent CYP3A inhibitors would require a longer duration of dosing (≥1 month). When considering 4βHC as a metric, one should take into account assay precision, the anticipated magnitude of the effect, and the feasibility of dosing beyond 2 weeks. In addition, the 4βHC metric needs to be normalized with the corresponding cholesterol plasma level in the same subject.
authors.affiliation: Metabolism and Pharmacokinetics, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002220:Carbamazepine / Q000008:administration & dosage / Q000494:pharmacology; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D008954:Models, Biological; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; C099828:cholest-5-ene-3,4-diol; D002220:Carbamazepine; D051544:Cytochrome P-450 CYP3A; D012293:Rifampin