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.

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.

These findings suggest that the CYP3A4*22, CYP3A5*3, and POR*28 variant alleles are of limited importance for overall individual variability in 4βOHC levels compared to nongenetic factors.

The present study shows that 4βOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4βOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism.

Recent studies have shown that the cytochrome P450 (CYP) 3A phenotype marker 4β‐hydroxycholesterol/cholesterol (4βOHC/C) ratio is negatively correlated with body weight in healthy volunteers, and that obese patients have lower 4βOHC levels than healthy controls. However, 4βOHC/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 4βOHC/C ratio. Furthermore, we wished to describe any association between body mass index (BMI) and 4βOHC/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 4βOHC/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). 4βOHC/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 4βOHC/C and BMI, which has previously been reported between 4βOHC/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.

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Systemic inflammation has been linked to suppressed CYP3A(4) activity. We determined 4β‐hydroxycholesterol (4βOHC), an endogenous CYP3A4 metabolite, in patients with rheumatoid arthritis (RA) before and after treatment with biological disease‐modifying antirheumatic drugs (bDMARDs). The 4βOHC was compared in 41 patients before and 2–5 months after initiating TNFα inhibitors (n = 31), IL‐6 inhibitors (n = 5), or B‐cell inhibitors (n = 5). Correlations between 4βOHC and inflammatory markers (C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR)) were also tested before and after bDMARDs. 4βOHC did not differ following bDMARD treatment (P = 0.6), nor in patients who started with IL‐6 inhibitors (median 51.6 vs. 50.6 nmol/L). The 4βOHC and CRP/ESR did not correlate before treatment (P > 0.5), but correlated significantly after bDMARDs (CRP = Spearman r ‐0.40; P < 0.01; ESR = r ‐0.34; P = 0.028) suggesting that mainly non‐CYP3A4‐suppressive cytokines were reduced during treatment. Thus, this study does not support a generally regained CYP3A4 phenotype in patients with RA following initiation of bDMARDs.

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