Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance

Abstract

Introduction: Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity.

Methods: Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day).

Results: A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant.

Conclusions: Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

Fig. 1

Groupwise longitudinal overview of change in a total body weight, b high-sensitive C-reactive protein (hsCRP) and c predicted liver fat percentage. For the Roux-en-Y gastric bypass (RYGB) and diet groups, linear mixed model predicted marginal mean and 95% confidence intervals are presented. For the normal-to-overweight control group, observed mean and 95% confidence interval is presented. Comparisons are made between the RYGB and diet groups at each visit, and significant differences are denoted with asterisks. Non-significant differences are not shown *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 2

Comparisons of rosuvastatin a oral clearance, b maximum concentration (C_max) and c time to maximum concentration (T_max) between patients with severe obesity and a normal- to overweight control group at baseline *p < 0.05; **p < 0.01; ***p < 0.001

Fig. 3

Between-group differences in within-group change for the Roux-en-Y gastric bypass (RYGB) and diet groups for a oral clearance (CL/F), b maximum concentration (C_max) and c time to maximum concentration (T_max). Difference between groups are made with the RYGB group as reference (positive values indicate greater change in the RYGB group), and are presented as marginal mean with 95% confidence interval

Fig. 4

Longitudinal overview of linear mixed effects model predicted oral clearance for individuals expressing the reduced function variant SLCO1B1 c.521CC and TC compared with c.521TT in the a Roux-en-Y gastric bypass (RYGB) and b diet groups, respectively. Data are presented as marginal mean with 95% confidence interval. The between-variant difference in within-variant change for the individuals with SLCO1B1 c.521TT or TC genotype compared with c.521TT are shown for the c RYGB and d diet group, presented as marginal mean with 95% confidence interval, with c.521TT as the reference group (positive values indicate greater change in patients with c.521TT)