title: Proximal Roux-en-Y gastric bypass alters drug absorption pattern but not systemic exposure of CYP3A4 and P-glycoprotein substrates.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  Prospective, nonblinded, longitudinal, single-dose pharmacokinetic study in three phases: presurgery baseline and postoperative assessments at 3 and 12 months.
  
  
  METHODS
  Twelve obese patients meeting current standards for bariatric surgery.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, Washington.
authors.forename: Lingtak-Neander
authors.initials: LN
authors.lastname: Chan
authors.forename: Yvonne S
authors.initials: YS
authors.lastname: Lin
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Tay-Sontheimer
authors.forename: Dorothy
authors.initials: D
authors.lastname: Trawick
authors.forename: Brant K
authors.initials: BK
authors.lastname: Oelschlager
authors.forename: David R
authors.initials: DR
authors.lastname: Flum
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Patton
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: John R
authors.initials: JR
authors.lastname: Horn
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics*; D005260:Female; D015390:Gastric Bypass / Q000009:adverse effects*; D065569:Gastrointestinal Absorption; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000601:surgery; D010865:Pilot Projects; D011446:Prospective Studies
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: CYP3A4; P-glycoprotein; Roux-en-Y gastric bypass; absorption; bariatric surgery; obesity; pharmacokinetics