title: 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 < 0.01). 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.
authors: Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands; Department of Clinical Pharmacy St. Antonius Hospital Nieuwegein The Netherlands.
authors: M J E
authors: MJ
authors: Brill
authors: Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands.
authors: P A J
authors: PA
authors: Välitalo
authors: Manchester Pharmacy School, University of Manchester Manchester Great Britain United Kingdom.
authors: A S
authors: AS
authors: Darwich
authors: Department of Surgery St. Antonius Hospital Nieuwegein The Netherlands.
authors: B
authors: B
authors: van Ramshorst
authors: Department of Anaesthesiology Intensive Care, and Pain Management, St. Antonius Hospital Nieuwegein The Netherlands.
authors: H P A
authors: HP
authors: van Dongen
authors: Manchester Pharmacy School, University of Manchester Manchester Great Britain United Kingdom.
authors: A
authors: A
authors: Rostami-Hodjegan
authors: Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands.
authors: M
authors: M
authors: Danhof
authors: Division of Pharmacology Leiden Academic Centre for Drug Research, Leiden University Leiden The Netherlands; Department of Clinical Pharmacy St. Antonius Hospital Nieuwegein The Netherlands.
authors: C A J
authors: CA
authors: Knibbe
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000737:chemistry / Q000201:enzymology; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008954:Models, Biological; D009767:Obesity, Morbid / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery*; D064887:Observational Studies as Topic
chemical_list: C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam