Proximal Roux-en-Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-glycoprotein substrates

Abstract

Study objectives: To evaluate the effect of Roux-en-Y gastric bypass surgery (RYGB) on the pharmacokinetics of midazolam (a CYP3A4 substrate) and digoxin (a P-glycoprotein substrate).

Design: Prospective, nonblinded, longitudinal, single-dose pharmacokinetic study in three phases: presurgery baseline and postoperative assessments at 3 and 12 months.

Patients: Twelve obese patients meeting current standards for bariatric surgery.

Measurements and main results: At each study visit, patients received a single dose of oral digoxin and midazolam at 8 a.m. Blood samples were collected at regular intervals for 24 hours after dosing. Continuous 12-lead electrocardiogram (EKG), heart rate, blood pressure, and respiratory rate were monitored, and pharmacokinetic parameters from the three visits were compared. The peak plasma concentration (Cmax ) of midazolam increased by 66% and 71% at 3- and 12-month post-RYGB (p=0.017 and p=0.001, respectively), whereas the median time to peak concentration (Tmax ) was reduced by 50%. The mean Cmax for 1'-hydroxymidazolam increased by 87% and 80% at 3 and 12 months (p=0.001 and p<0.001, respectively). However, neither the area under the concentration-time curve (AUC) for midazolam nor the metabolite-to-parent AUC ratio changed significantly over time. For digoxin, the median Tmax decreased from 40 minutes at baseline to 30 and 20 minutes at 3 and 12 months, respectively. The mean AUC for digoxin, heart rate, and EKG patterns were similar across the three study phases.

Conclusion: Contemporary proximal RYGB increases the rate of drug absorption without significantly changing the overall exposure to midazolam and digoxin. The Cmax of a CYP3A4 substrate with a high extraction ratio was substantially increased after RYGB.

Keywords: CYP3A4; P-glycoprotein; Roux-en-Y gastric bypass; absorption; bariatric surgery; obesity; pharmacokinetics.

Figure 1

Plasma midazolam concentration versus time profiles in patients undergoing Roux-en-Y gastric bypass. Open, gray, and black circles represent presurgical baseline, 3- and 12-month postoperative study days, respectively.

Figure 2

Plasma 1′-hydroxymidazolam concentration versus time profiles in patients undergoing Roux-en-Y gastric bypass. Open, gray, and black circles represent presurgical baseline, 3- and 12-month postoperative study days, respectively.

Figure 3

Plasma digoxin concentration versus time profiles in patients undergoing Roux-en-Y gastric bypass. Open, gray, and black circles represent presurgical baseline, 3- and 12-month postoperative study days, respectively.