Short‐ and long‐term effects of body weight loss following calorie restriction and gastric bypass on CYP3A‐activity – a non‐randomized three‐armed controlled trial

Abstract

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.

Drug Disposition Protein Quantification in Matched Human Jejunum and Liver From Donors With Obesity

“… 50 , 53 , 54 We recently showed correlations between liver CYP3A4 and body weight for our 37 donors with obesity together with the lower weight control group. 55 In contrast, we found no difference in hepatic uptake clearance of rosuvastatin and body weight in the same donors. 3 Furthermore, using the published model 3 and the protein levels of the transporters SLCO1B1, SLCO2B1, SLCO1B3, and SLC10A1, we found no difference in predicted area under the curve vs. concentration (AUC; ng/mL/h) of rosuvastatin in the 37 donors with obesity and the 17 lower weight donors (median AUC (25th–75th percentiles): 3159.6 (2,659.7–4,932.8) ng/mL/h and 3,497.8 (3,027.7–4,462.5) ng/mL/h), respectively.…”

“…Furthermore, it is difficult to study individual biological factors in a physiologically relevant manner 50,53,54 . We recently showed correlations between liver CYP3A4 and body weight for our 37 donors with obesity together with the lower weight control group 55 . In contrast, we found no difference in hepatic uptake clearance of rosuvastatin and body weight in the same donors 3 .…”

Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range

“…In total, 96 patients from the open-label, three-armed COCKTAIL-study (NCT02386917) were included in the present analysis [36,37]. The study population included 78 patients with severe obesity (BMI -> 40 or 35-40 kg/ m 2 combined with at least one obesity-related comorbidity) scheduled for weight loss treatment with Rouxen-Y-gastric bypass (RYGB) (n = 38) or non-surgical calorie restriction (n = 40), and 18 mainly normal to overweight individuals scheduled for cholecystectomy (BMI 18.5-30 kg/m 2 ).…”

“…Blood samples for determination of midazolam plasma concentrations were collected from a peripheral venous catheter before and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 2.5, 5, 5.5, 6, 8, 10, 12, 23, and 24 h following oral dosing. The pharmacokinetic investigation has been described in more detail previously [37]. In vivo midazolam pharmacokinetic data were available in 92 patients.…”

“…However, since midazolam is a medium-to-high extraction ratio drug, systemic clearance may be affected by changes in protein binding, hepatic blood flow, and intrinsic clearance (CL int ), the latter representing metabolic capacity [17][18][19]. Previous studies have suggested that midazolam pharmacokinetics may be influenced by an increased hepatic blood flow in patients with obesity [20,21]. Thus, in selected patient populations, the use of midazolam for CYP3A4 phenotyping may be challenging as it does not necessarily reflect CYP3A4 activity.…”