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.

The influence of bariatric surgery on oral drug bioavailability in patients with obesity: A systematic review

“…RYGBP was the predominant surgical procedure (n = 18) . In one study, BPD was investigated as the surgical procedure, while two studies investigated BPD‐DS, six studied SG, and one included jejunoileostomy …”

“…Midazolam undergoes hydroxylation via both intestinal and hepatic CYP3A and is the most commonly used probe drug to investigate in vivo CYP3A activity . The effects on midazolam pharmacokinetics were explored in three of the studies that make up this systematic review . In one of these studies, absolute bioavailability and clearance were assessable because of a combined oral and intravenous administration of midazolam .…”

“…These sophisticated analyses suggested that hepatic intrinsic clearance increased 1.5‐fold following bariatric surgery, whereas the intrinsic metabolism of midazolam in the gut wall was low and highly variable . Following oral dosing of midazolam, the rate of absorption was faster both in the short term (3 mo) and long term (12 mo) after surgery …”

Oral Contraceptives after Bariatric Surgery

“…Chan et al [54] compared the pattern and magnitude of oral absorption of digoxin in obese patients before and after RYGB. The median time to peak concentration for digoxin decreased from 40 min at baseline to 30 and 20 min at 3 and 12 months after RYGB, respectively.…”

“…Chan et al [54] compared the pattern and magnitude of oral absorption of midazolam in obese patients before and after RYGB. The peak plasma concentration (Cmax) of midazolam increased by 66% and 71% at 3 and 12 months after RYGB, respectively, whereas the median time to peak concentration was reduced by 50%.…”