Semiphysiologically Based Pharmacokinetic Model for Midazolam and CYP3A Mediated Metabolite 1-OH-Midazolam in Morbidly Obese and Weight Loss Surgery Patients

被引：31

作者：

Brill, M. J. E. ^{[1
,2
]}

Valitalo, P. A. J. ^{[1
]}

Darwich, A. S. ^{[3
]}

van Ramshorst, B. ^{[4
]}

van Dongen, H. P. A. ^{[5
]}

Rostami-Hodjegan, A. ^{[3
]}

Danhof, M. ^{[1
]}

Knibbe, C. A. J. ^{[1
,2
]}

机构：

[1] Leiden Univ, Leiden Acad Ctr Drug Res, Div Pharmacol, Leiden, Netherlands

[2] St Antonius Hosp, Dept Clin Pharm, Nieuwegein, Netherlands

[3] Univ Manchester, Manchester Pharm Sch, Manchester, Great Britain, England

[4] St Antonius Hosp, Dept Surg, Nieuwegein, Netherlands

[5] St Antonius Hosp, Dept Anaesthesiol Intens Care & Pain Management, Nieuwegein, Netherlands

来源：

CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY | 2016年 / 5卷 / 01期

关键词：

D O I：

10.1002/psp4.12048

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

This study aimed to describe the pharmacokinetics of midazolam and its cytochrome P450 3A (CYP3A) mediated metabolite 1OH- 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.

引用

页码：20 / 30

页数：11

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