Frances-Fernandez, E., Mangas-Sanjuan,V., Piqueras M., Gonzalez-Alvarez, M, Gonzalez-Alvarez, I, Bermejo, M.
Pharmacokinetics and Pharmaceutical Technology Area, Department of Engineering, Miguel Hernandez University (Spain)
Introduction: Clavulanic acid is a beta-lactamase inhibitor and it has been coadministered orally with amoxicillin since 1981 for different infections treatment. It is metabolized extensively in the liver, 1 hour half-life and it shows around 30-40% renal excretion. It is ionized through the gastrointestinal tract (pKa 2.7).
Objective: The aim of this work is to establish the absorption mechanisms involved in the absorption of clavulanic acid in the small intestine after in situ experiments.
Materials and Methods: An in situ perfusion method without recirculation described by Doluisio [1] and adapted to our experimental conditions was used to determine the absorption mechanism involved using male Wistar rats (270-300g). In situ experiments were performed at 0.25, 0.625, 1.25 and 2.5 M of clavulanic acid in duodenum, jejunum and ileum. Permeability rate coefficients were estimated by non-linear regression of decreasing concentrations in lumen. The fitting procedures were performed using NONMEM 7.2 with FOCE+I for objective function estimation and ADVAN13 subroutine [2]. For graphical and statistical analysis, the R software was used. Pc-VPC [3] and bootstrap analysis were performed using PsN and Xpose version 4.5.3.
Results: The analysis of in situ data were well modeled using a common compartment for all intestinal segments. The best model able to describe the observations obtained was a passive diffusion in all three segments of the small intestine with an active absorption transporter in the duodenum. All parameters in the model were estimated with good precision based on the values of the results from the bootstrap analysis. The population model provides a proper description of the drug concentration data, based on GOF and pc-VPC.
Conclusions: Clavulanic acid shows a passive diffusion absorption combined with an active absorption transporter in the duodenum segment of the small intestine. Based on pharmacokinetic parameters obtained, the absorption is mainly involved in the first segment (duodenum) of the small intestine. The higly variable absorption related to clavulanic acid might be caused because of the gastric emptying frequence, due to duodenum is the most relevant segment involved in the absorption of clavulanic acid.Further studies incorporating the degradation process involved through the gastrointestinal tract may contribute to explain differences observed in the in vivo absorption.
References:
[1] Doluisio, J.T., Billups, N.F., Dittert, L.W., Sugita, E.T., Swintosky, J.V., 1969. Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. J Pharm Sci 58, 1196-1200.
[2] Bauer R (2011) NONMEM users guide: introduction to NONMEM 7.2.0. . ICON Development Solutions, Ellicott City.
[3] Bergstrand M, Hooker AC, Wallin JE and Karlsson MO (2011) Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. The AAPS journal 13:143-151.
Reference: PAGE 24 (2015) Abstr 3478 [www.page-meeting.org/?abstract=3478]
Poster: Drug/Disease modeling - Absorption & PBPK