LAUSR

AIM Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 (CYP) 1A2-activity), 5-hydroxyomeprazole/omeprazole (CYP2C19-activity) and losartan/losartan carboxylic acid (CYP2C9-activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. METHODS This trial included patients with severe obesity preparing for RYGB (n=40) 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, week 0-3) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day, week 3-9). Follow-up-time was two years, with four pharmacokinetic investigations. RESULTS Mean±SD weight loss from baseline was similar in the RYGB-group (13±2.4%) and diet-group (10.5±3.9%) at week 9, but differed at year 2 (RYGB: -30±6.9%, diet: -3.1±6.3%). From week 0-3, mean [95% CI] CYP2C19-activity similarly increased in both groups (RYGB: 43% [16, 55], diet: 48% [22, 60]). Mean CYP2C19-activity increased by 30% [2.6, 43] after RYGB (week 3-9), but not in the diet-group, between-group difference: -0.30 [-0.63, 0.03]. CYP2C19-activity remained elevated in the RYGB-group at year 2. Baseline CYP2C19-activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2- and CYP2C9-activity. CONCLUSION Our findings suggest that CYP2C19-activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2- and CYP2C9-activity were observed.