It remains uncertain whether pharmacokinetic changes following Roux‐en‐Y gastric bypass (RYGB) can be attributed to surgery‐induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short‐ and long‐term effects of RYGB and calorie restriction on CYP3A‐activity, and cross‐sectionally compare CYP3A‐activity with normal weight to overweight controls using midazolam as probe drug. This three‐armed controlled trial included patients with severe obesity preparing for RYGB ( n = 41) or diet‐induced ( n = 41) weight‐loss, and controls ( n = 18). Both weight‐loss groups underwent a 3‐week low‐energy‐diet (<1200 kcal/day) followed by a 6‐week very‐low‐energy‐diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight‐loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between‐group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A‐activity is not only dependent on weight‐loss through RYGB.

Purpose Poor metabolizers (PMs) of the highly polymorphic enzyme CYP2D6 are usually at high risk of adverse effects during standard recommended dosing of CYP2D6-metabolized drugs. We studied if the metabolism of solanidine, a dietary compound found in potatoes, could serve as a biomarker predicting the CYP2D6 PM phenotype for precision dosing. Methods The study included 839 CYP2D6-genotyped patients who were randomized by a 4:1 ratio into test or validation cohorts. Full-scan high-resolution mass spectrometry data files of previously analyzed serum samples were reprocessed for identification and quantification of solanidine and seven metabolites. Metabolite-to-solanidine ratios (MRs) of the various solanidine metabolites were calculated prior to performing receiver operator characteristic (ROC) and multiple linear regression analyses on the test cohort. The MR thresholds obtained from the ROC analyses were tested for the prediction of CYP2D6 PMs in the validation cohort. Results In the test cohort, the M414-to-solanidine MR attained the highest sensitivity and specificity parameters from the ROC analyses (0.98 and 1.00) and highest explained variance from the linear models (R2 = 0.68). Below these thresholds, CYP2D6 PM predictions were tested in the validation cohort providing positive and negative predictive values of 100% for the MR of M414, while similar values for the other MRs ranged from 20.5 to 73.3% and 96.7 to 99.3%, respectively. Conclusion The M414-to-solanidine MR is an excellent predictor of the CYP2D6 PM phenotype. By measuring solanidine and metabolites using liquid chromatography-mass spectrometry in patient serum samples, CYP2D6 PMs can easily be identified, hence facilitating the implementation of precision dosing in clinical practice.

Characterizing the pharmacokinetic properties of drug candidates represents an essential task during drug development. In the past, liver microsomes and primary suspended hepatocytes have been extensively used for this purpose, but their relatively short stability limits the applicability of such in vitro systems for drug compounds with low metabolic turnover. In the present study, we used 3D primary human hepatocyte spheroids to predict the hepatic clearance of seven drugs with low to intermediate clearance in humans. Our results indicate that hepatocyte spheroids maintain their in vivo like phenotype during prolonged incubations allowing to monitor the depletion of parent drug for seven days. In This article has not been copyedited and formatted. The final version may differ from this version.

This study shows that phenytoin and carbamazepine have approximately twice the CYP3A4-inducing potency of phenobarbital. The results indicate that 2-fold higher doses of CYP3A4-metabolized drugs may generally be required during concurrent treatment with phenytoin or carbamazepine compared with phenobarbital.