Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4ß-Hydroxycholesterol-an Interaction Study in Healthy Volunteers.

4ß-Hydroxycholesterol (4ßOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4ßOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4ßOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4ßOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4ßOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1 week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4ßOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.

Elevated 4ß-hydroxycholesterol/cholesterol ratio in anorexia nervosa patients.

Recent studies have shown that the cytochrome P450 (CYP) 3A phenotype marker 4ß-hydroxycholesterol/cholesterol (4ßOHC/C) ratio is negatively correlated with body weight in healthy volunteers, and that obese patients have lower 4ßOHC levels than healthy controls. However, 4ßOHC/C ratio in underweight patients has yet to be reported. The aim of this study was to examine potential differences in CYP3A activity between underweight patients with anorexia nervosa and normal-weight volunteers by measuring plasma 4ßOHC/C ratio. Furthermore, we wished to describe any association between body mass index (BMI) and 4ßOHC/C ratio in underweight patients. A total of 20 underweight patients and 16 normal-weight volunteers were included in the study, all females. Underweight patients had a median 4ßOHC/C ratio (molar ratio × 10-5) of 2.52 (range, 0.90-11.3) compared to 1.29 (0.56-2.09) in normal-weight subjects (Mann-Whitney P = 0.0005). 4ßOHC/C ratio was negatively correlated with BMI in underweight patients (r = -0.56, P = 0.011), and in the whole study population (r = -0.67, P < 0.0001). This suggests that the negative correlation between 4ßOHC/C and BMI, which has previously been reported between 4ßOHC/C and body weight in healthy volunteers, extends to underweight patients. The findings indicate that CYP3A activity increases with decreasing BMI, resulting in higher CYP3A activity in underweight patients compared to normal-weight subjects. The potential clinical relevance of this needs to be studied further by comparing pharmacokinetics of drugs subjected to CYP3A-mediated metabolism in underweight vs. normal-weight individuals.

4ß-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients.

AIM: 4ß-Hydroxycholesterol (4ßOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4ßOHC levels and steady-state concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients. METHODS: Serum samples from 151 patients treated with quetiapine as immediate release (IR; n = 98) or slow release (XR; n = 53) tablets were included for analysis of 4ßOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 h post-dosing for IR and XR tablets, respectively. Correlations between 4ßOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (≥60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis. RESULTS: Correlations between 4ßOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P < 0.0001). Estimated Spearman r values were -0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4ßOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P < 0.001), including gender (P = 0.023) and age (P = 0.003) as significant covariates. CONCLUSIONS: The present study shows that 4ßOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4ßOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.

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

AIM: 4ß-hydroxycholesterol (4ßOHC) 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 4ßOHC 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. 4ßOHC 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 4ßOHC concentration and daily dose and Css of carbamazepine, respectively, were performed by Spearman's tests. In addition, 4ßOHC concentrations in females vs. males were compared in induced and non-induced patients. RESULTS: Median 4ßOHC 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 4ßOHC concentration (Spearman r = 0.53, 95% confidence interval [CI] 0.27, 0.72, P < 0.001). No significant correlation between carbamazepine Css and 4ßOHC concentration was found (Spearman r = 0.14; 95% CI -0.14, 0.40, P = 0.3). Enzyme-induced females had significantly higher 4ßOHC concentrations than males (P < 0.001), while no significant gender difference was found in non-induced patients (P = 0.52). CONCLUSION: Serum concentrations of 4ßOHC 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 4ßOHC formation. Moreover, CYP3A4 inducibility seems to be higher in females than males.

Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline.

BACKGROUND: The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. METHODS: Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. RESULTS: Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P < 0.001), esomeprazole (+32.8%; P < 0.001), and lansoprazole (+14.7%; P = 0.043). Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P < 0.001), esomeprazole (+81.8%; P < 0.001), lansoprazole (+20.1%; P = 0.008), and pantoprazole (+21.6%; P = 0.002). Sertraline concentrations were significantly higher in patients treated with esomeprazole (+38.5%; P = 0.0014). CONCLUSIONS: The effect of comedication with PPIs on the serum concentration of SSRIs is more pronounced for omeprazole and esomeprazole than for lansoprazole and pantoprazole, and escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered.