Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
Br J Clin Pharmacol. 2022 Sep;88(9):4121-4133. doi: 10.1111/bcp.15349. Epub 2022 Apr 25.
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.
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, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations.
Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB -30 ± 6.9%, diet -3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [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 (weeks 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 activities.
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 activities was observed.
Roux-en-Y 胃旁路术（RYGB）可能会影响药物处置，这是由于手术引起的胃肠道改变和/或随后的体重减轻。目的是比较 RYGB 和饮食对间黄嘌呤/咖啡因（细胞色素 P450 [CYP] 1A2 活性）、5-羟奥美拉唑/奥美拉唑（CYP2C19 活性）和洛沙坦/洛沙坦羧酸（CYP2C9 活性）的短期和长期影响，并与正常至超重对照组进行横断面比较这些 CYP 活性。
本试验包括准备接受 RYGB（n=40）或饮食诱导（n=41）减肥的严重肥胖患者，以及对照组（n=18）。两组减肥患者均接受为期 3 周的低能量饮食（<1200 千卡/天，第 0-3 周），然后进行为期 6 周的极低能量饮食或 RYGB（均<800 千卡/天，第 3-9 周）。随访时间为 2 年，进行了 4 次药代动力学研究。
第 9 周时，RYGB 组（13±2.4%）和饮食组（10.5±3.9%）的体重减轻平均值（±标准差）与基线相似，但在第 2 年时有所不同（RYGB-30±6.9%，饮食-3.1±6.3%）。从第 0 周到第 3 周，两组 CYP2C19 活性均相似增加（RYGB 43%[16,55]，饮食 48%[22,60]）。RYGB 后 CYP2C19 活性增加 30%（2.6,43）（第 3-9 周），但饮食组无变化（组间差异-0.30[-0.63,0.03]）。RYGB 组在第 2 年时 CYP2C19 活性仍升高。与肥胖患者相比，对照组的 CYP2C19 活性高 2.7 倍，而 CYP1A2 和 CYP2C9 活性无差异。
我们的研究结果表明，肥胖患者的 CYP2C19 活性较低，减肥后会增加。这可能与药物剂量有关。未观察到 CYP1A2 和 CYP2C9 活性的临床显著影响。
