Dataset Information

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

ABSTRACT: 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??0.05), 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.

SUBMITTER: Brill MJ

PROVIDER: S-EPMC4728292 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Brill M J E MJ Välitalo P A J PA Darwich A S AS van Ramshorst B B van Dongen H P A HP Rostami-Hodjegan A A Danhof M M Knibbe C A J CA

CPT: pharmacometrics & systems pharmacology 20151218 1

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, intrins ...[more]

PMID: 26844012

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Project description:IntroductionBariatric surgery performed at high volume centers decreases length of stay, cost, and morbidity and mortality. The effect of a high volume of bariatric surgery procedures on outcomes may extend not just to bariatric surgery but to any general surgical procedure in morbidly obese patients. We hypothesized that patients with morbid obesity (body mass index >40 kg/m2) undergoing common, nonbariatric general surgery would have decreased morbidity and mortality at centers performing high volumes of bariatric surgery.MethodsThe 2016 National Inpatient Sample (NIS) was used to identify the number of laparoscopic gastric bypass and sleeve gastrectomy performed at each hospital. Hospitals were classified as high volume bariatric hospitals (HVBH) ≥10 reported cases (50 actual)/year or low volume bariatric hospitals (LVBH) <10 reported cases (50 actual)/year, as NIS reports a 20% sample of actual cases. Patients with morbid obesity undergoing laparoscopic or open appendectomy, cholecystectomy, or ventral hernia repair were included for analysis. Propensity scores were developed based on available demographics, comorbidities, and hospital procedure volume. Postoperative complications during the index hospital admission, determined by ICD-10 code, were compared using inverse propensity weights. Differences were considered significant with a p value of <0.05.ResultsThe total number of general surgery patient cases analyzed was 14,028 from 2,482 hospitals, representing 70,140 admissions. The cohort of patients undergoing operations treated at HVBH were younger (p=0.03) with higher rates of COPD (p=0.04). Patients at LVBH had higher rates of nicotine dependence (p=0.0001) and obstructive sleep apnea (p < 0.001). On propensity-weighted analysis adjusting for preoperative comorbidities and hospital procedure volume, there were significantly higher rates of multiple postprocedure complications at LVBH, specifically, postprocedure respiratory failure for patients undergoing elective laparoscopic cholecystectomy, elective ventral hernia repair with mesh and appendectomy.ConclusionPatients with morbid obesity may have an advantage in having general surgery procedures at HVBH. HVBH may have a volume-outcomes relationship where the hospital and staff familiarity with the management principles required to minimize the postoperative risk associated with morbid obesity and improve patient outcomes.

Dataset Information

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

Publications

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

Similar Datasets

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