title: The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients Before and One Year After Bariatric Surgery.
abstract: OBJECTIVE
  Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m(2)). As information about the effects of this procedure on a drug's pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery.
  
  
  METHODS
  Twenty morbidly obese patients (aged 26-58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 ± 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling.
  
  
  RESULTS
  One year after bariatric surgery, systemic clearance of midazolam was higher [0.65 (7%) versus 0.39 (11%) L/min, mean ± RSE (P < 0.01), respectively] and mean oral transit time (MTT) was faster [23 (20%) versus 51 (15%) minutes (P < 0.01)], while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (P < 0.05).
  
  
  CONCLUSIONS
  In this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.|Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
authors.forename: Margreke J
authors.initials: MJ
authors.lastname: Brill
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.|Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands.
authors.forename: Anne
authors.initials: A
authors.lastname: van Rongen
authors.affiliation: Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Eric P
authors.initials: EP
authors.lastname: van Dongen
authors.affiliation: Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.affiliation: Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hazebroek
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester, Great Britain, UK.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Darwich
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester, Great Britain, UK.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. c.knibbe@antoniusziekenhuis.nl.|Department of Clinical Pharmacy, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands. c.knibbe@antoniusziekenhuis.nl.
authors.forename: Catherijne A
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D050110:Bariatric Surgery; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D008875:Middle Aged; D009767:Obesity, Morbid / Q000097:blood* / Q000378:metabolism* / Q000601:surgery; D011446:Prospective Studies
chemical_list: D014151:Anti-Anxiety Agents; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam
keywords: CYP3A; bariatric surgery; midazolam; pharmacokinetics