Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations.
OBJECTIVE
The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.


METHODS
A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB.


RESULTS
After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity.


CONCLUSIONS
The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Ina
I
Gesquiere
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Adam S
AS
Darwich
Clinical and Experimental Endocrinology, KU Leuven and Department of Endocrinology, University Hospitals Leuven/KU Leuven, Campus Gasthuisberg, Leuven, Belgium.
Bart
B
Van der Schueren
Center for Clinical Pharmacology, University Hospitals Leuven/KU Leuven, Campus Gasthuisberg, Leuven, Belgium.
Jan
J
de Hoon
Department of Abdominal Surgery, University Hospitals Leuven/KU Leuven, Campus Gasthuisberg, Leuven, Belgium.
Matthias
M
Lannoo
Clinical and Experimental Endocrinology, KU Leuven and Department of Endocrinology, University Hospitals Leuven/KU Leuven, Campus Gasthuisberg, Leuven, Belgium.
Christophe
C
Matthys
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Amin
A
Rostami
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Veerle
V
Foulon
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Patrick
P
Augustijns
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D003198:Computer Simulation; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D015390:Gastric Bypass; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008954:Models, Biological
D003692:Delayed-Action Preparations; D008790:Metoprolol
Roux-en-Y gastric bypass; controlled release; disposition; formulation; metoprolol; modelling