Pharmacokinetic and Pharmacodynamic Alterations in the Roux-en-Y Gastric Bypass Recipients

Tandra, Sweta; Chalasani, Naga; Jones, David R.; Mattar, Samer G.; Hall, Stephen D.; Vuppalanchi, Raj

doi:10.1097/sla.0b013e31827a0e82

Cited by 60 publications

(72 citation statements)

References 46 publications

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“…Although the overall apparent oral clearance of midazolam was unchanged at the 3‐ and 12‐month visits after RYGB, peak concentrations were significantly higher at both postoperative time points. This finding differs from the results of another study that examined oral midazolam bioavailability after RYGB . Another study also reported that the T max of oral midazolam was decreased but did not find significant changes in C max or AUC.…”

Section: Discussioncontrasting

confidence: 93%

“…It compared the pharmacokinetics of midazolam in RYGB recipients with nonsurgical control subjects. Moreover, it collected fewer blood samples during the midazolam absorption phase and may have missed the actual T max and C max . Because midazolam was administered as an oral liquid in both studies, one would expect the time to reach C max to be within 10–15 minutes after drug administration in the postoperative patients.…”

Section: Discussionmentioning

confidence: 99%

“…The altered anatomy in the upper GI tract after RYGB suggests that the pharmacokinetic profile of drugs, especially during the absorption phase, may be changed. Currently, very few studies have addressed this issue, and their results are conflicting . Research conducted in the last decade has also provided insight into the physiology of the small intestine, which is now considered to be important in regulating the oral absorption of both drugs and nutrients.…”

mentioning

confidence: 99%

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Proximal Roux‐en‐Y Gastric Bypass Alters Drug Absorption Pattern But Not Systemic Exposure of CYP3A4 and P‐glycoprotein Substrates

et al. 2015

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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.

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Section: Discussioncontrasting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Proximal Roux‐en‐Y Gastric Bypass Alters Drug Absorption Pattern But Not Systemic Exposure of CYP3A4 and P‐glycoprotein Substrates

et al. 2015

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“…Previously, we showed in a population pharmacokinetic (PK) analysis that plasma clearance (CL) of the cytochrome P450 3A (CYP3A) substrate midazolam is 1.7 times increased in patients after a weight loss procedure in comparison to morbidly obese patients, whereas oral bioavailability (F total ) was unaltered . Similar results have been reported before for RYGB patients in comparison with age, gender, and body mass index‐matched control patients . Although it is well known that CYP3A resides both in the gut and in the liver, these analyses that use total oral bioavailability (F total ) as parameter do not allow for a distinction between the contribution of presystemic gut and presystemic liver metabolism.…”

supporting

confidence: 78%

Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1‐OH‐midazolam in morbidly obese and weight loss surgery patients

Brill

Välitalo

Darwich

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1‐OH‐midazolam in morbidly obese patients receiving oral and i.v. midazolam before (n = 20) and one year after weight loss surgery (n = 18), thereby providing insight into the influence of weight loss surgery on CYP3A activity in the gut wall and liver. In a semiphysiologically based pharmacokinetic (semi‐PBPK) model in which different blood flow scenarios were evaluated, intrinsic hepatic clearance of midazolam (CLint,H) was 2 (95% CI 1.40–1.64) times higher compared to morbidly obese patients before surgery (P < 0.01). Midazolam gut wall clearance (CLint,G) was slightly lower in patients after surgery (P > 0.05), with low values for both groups. The results of the semi‐PBPK model suggest that, in patients after weight loss surgery, CYP3A hepatic metabolizing capacity seems to recover compared to morbidly obese patients, whereas CYP3A mediated CLint,G was low for both populations and showed large interindividual variability.

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“…A subsequent matched cohort study from the same group showed that RYGB patients required higher doses of sedation during EGD than the non-RYGB with similar age, gender and BMI [31]. Authors hypothesized that these findings could be due to an improvement in liver function after gastric bypass, which resulted in an improvement in liver metabolism of fentanyl and midazolam, which subsequently led to increased requirement of both sedatives during EGD [32–33]. …”

Section: Obesity and Sedationmentioning

confidence: 99%

Sedation Challenges

Jirapinyo

Thompson

2016

Gastrointestinal Endoscopy Clinics of North America

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Pharmacokinetic and Pharmacodynamic Alterations in the Roux-en-Y Gastric Bypass Recipients

Abstract: RYGB recipients have significantly shorter tmax for the studied orally administered medications, but otherwise no other significant changes in PK were reported.

Cited by 60 publications

References 46 publications

Proximal Roux‐en‐Y Gastric Bypass Alters Drug Absorption Pattern But Not Systemic Exposure of CYP3A4 and P‐glycoprotein Substrates

Proximal Roux‐en‐Y Gastric Bypass Alters Drug Absorption Pattern But Not Systemic Exposure of CYP3A4 and P‐glycoprotein Substrates

Semiphysiologically based pharmacokinetic model for midazolam and CYP3A mediated metabolite 1‐OH‐midazolam in morbidly obese and weight loss surgery patients

Sedation Challenges

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