4β‐hydroxycholesterol correlates with dose but not steady‐state concentration of carbamazepine: indication of intestinal CYP3A in biomarker formation?

Abstract

Aim 4β‐hydroxycholesterol (4βOHC) is an endogenous CYP3A(4) biomarker, which is elevated by use of the CYP3A4 inducer carbamazepine. Our aim was to compare to what extent serum concentration of 4βOHC correlates with dose (presystemic exposure) and steady‐state concentration (systemic exposure) of carbamazepine. Methods The study was based on a therapeutic drug monitoring material, including information about daily doses and steady‐state concentrations (Css) of carbamazepine. 4βOHC concentrations were determined in residual serum samples of 55 randomly selected carbamazepine‐treated patients and 54 levetiracetam‐treated patients (negative controls) by UPLC‐APCI‐MS/MS after liquid–liquid extraction. Correlation analyses between 4βOHC concentration and daily dose and Css of carbamazepine, respectively, were performed by Spearman's tests. In addition, 4βOHC concentrations in females vs. males were compared in induced and non‐induced patients. Results Median 4βOHC concentration was ~10‐fold higher in carbamazepine‐ vs. levetiracetam‐treated patients (650 vs. 54 nmol l−1, P < 0.0001). There was a significant, positive correlation between carbamazepine dose and 4βOHC concentration (Spearman r = 0.53, 95% confidence interval [CI] 0.27, 0.72, P < 0.001). No significant correlation between carbamazepine Css and 4βOHC concentration was found (Spearman r = 0.14; 95% CI −0.14, 0.40, P = 0.3). Enzyme‐induced females had significantly higher 4βOHC concentrations than males (P < 0.001), while no significant gender difference was found in non‐induced patients (P = 0.52). Conclusion Serum concentrations of 4βOHC correlate with presystemic, but not systemic exposure of the CYP3A4 inducer carbamazepine. This suggests a stronger inductive effect of carbamazepine on presystemic than systemic CYP3A4 phenotype and might indicate a role of the intestine in 4βOHC formation. Moreover, CYP3A4 inducibility seems to be higher in females than males.

4β‐Hydroxycholesterol level significantly correlates with steady‐state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients

“…One previous study failed to show significant associations between 4βOHC levels and clearance estimates of the CYP3A4 substrates docetaxel and paclitaxel following intravenous administration [30]. This latter might reflect potential relevance of non-CYP3A4 mechanisms in clearance of docetaxel and paclitaxel, but in light of the possible role of intestinal CYP3A4 in biomarker formation [17], the intravenous administration of these substrates could also be a factor of relevance for the reported lack of associations with 4βOHC levels in that study.…”

“…30-50% higher in females than males), which provide clear evidence that basal CYP3A4 activity is higher in females than males. The underlying mechanism for the gender difference in CYP3A4 phenotype is uncertain, but we recently observed that females appeared to be more responsive towards induction of CYP3A4 activity during use of carbamazepine [17]. The higher basal CYP3A4 activity in females than males might therefore be due to greater responsiveness towards exogenous or endogenous factors increasing enzyme activity.…”

“…Several studies have shown that 4βOHC levels change significantly following administration of both CYP3A4 inducers and inhibitors . Change in 4βOHC level seems to be more sensitive towards CYP3A4 induction than inhibition, which possibly reflects its long elimination half‐life .…”

Elevated 4β‐hydroxycholesterol/cholesterol ratio in anorexia nervosa patients

“…Plasma concentration of 4βOHC was determined by a previously described UPLC‐MS/MS assay . The lower limit of quantification was 10 ng/mL.…”

“…The lower limit of quantification was 10 ng/mL. Intra‐ and interday imprecision and inaccuracy for the method were <15% at 10 ng/mL and <4% at 644 ng/mL (n = 6) . All samples were stored at −80°C between sampling and analysis.…”