Use of 4β-Hydroxycholesterol in Animal and Human Plasma Samples as A Biomarker for Cyp3A Induction

Abstract

These assays were applied to multiple studies and demonstrated potential applications of 4βHC as a CYP3A biomarker across preclinical and clinical settings.

Clinical Evaluation Based on a New Approach to Improve the Accuracy of 4β-Hydroxycholesterol Measurement as a Biomarker of CYP3A4 Activity

“…Interestingly, 4β-HC/TC ratios were significantly elevated at all dosage levels of JTE-451 and JTE-761 ( Table 2 and Figure 3 ). Similarly, previous studies have reported that 4β-HC/TC ratios fluctuate when CYP3A4 inducers are administered, although no study has been conducted for weak CYP3A4 inducers, to the best of our knowledge [ 4 , 5 , 6 , 7 , 27 ]. As cholesterol concentrations influence the generation of 4β-HC [ 16 , 28 ], we believe that 4β-HC/TC ratios are more suitable than 4β-HC concentrations when plasma cholesterol concentrations fluctuate, as was the case in this study ( Table 2 ); however, further clinical studies are needed to demonstrate that the use of 4β-HC/TC ratios are more practical for assessing CYP3A4 induction than 4β-HC concentrations, as there were certain limitations to this study (e.g., no placebo groups were set).…”

“…Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) plays a role in the metabolism (oxidation) of cholesterol to 4β-hydroxycholesterol (4β-HC, Figure 1 A) [ 1 , 2 ]. In support of this, many clinical studies have reported that the administration of CYP3A4 inducers (e.g., rifampicin, a strong inducer of CYP3A4) increases the concentration of 4β-HC (or 4β-HC/total cholesterol ratio (4β-HC/TC ratio)) in human plasma [ 3 , 4 , 5 , 6 , 7 ]; thus, 4β-HC is considered a potential marker for assessing the risk concerning whether a new chemical entity (NCE) induces CYP3A4 [ 8 ]. Although several clinical studies have assessed the above possibility using strong inducers of CYP3A4 (e.g., rifampicin) [ 3 , 4 , 5 , 6 , 7 ], further clinical studies, with various CYP3A4 inducers (especially weak inducers), are required.…”