Research paperTransintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies
Introduction
In recent years, the importance of the intestinal efflux mediated by several carriers has been shown. This process runs counter current to the absorptive transport or diffusion of drugs, restricting the extent of oral absorption [1], [2].
Many times this is the reason for the failure of predicting bioavailability from the structure [3]. A considerable effort has been made to identify the structural features that determine the interaction with this type of transporters [4], in order to avoid them in the design and development of new drugs. On the other hand, as pointed out by several authors such as Lentz [5], Doppenschmitt [6] and Stephens [7], affinity to P-glycoprotein (Pgp) observed in vitro does not always imply a reduction in the rate or extent of absorption, nor in the ‘in vivo’ activity since other factors such as passive permeability and gut wall metabolism will affect the overall performance of the drug.
There has been a great interest in studying possible inhibitors of the process as they would allow a better use of several drugs, mainly chemotherapeutic agents and anti-HIV drugs, whose resistance is based on the efflux at the target site by the same type of carriers [8], [9], [10].
Fluoroquinolones have been reported as a group of structures able to undergo efflux, which can explain the low bioavailability of some of them [11], [12]. The aim of the study is to test the influence of efflux on the absorption of three fluoroquinolones differing in effective permeabilities while maintaining the main structural features. This would allow us to gain an insight on the characteristics of this class of drugs that lead to interaction with intestinal transporters. The knowledge could be of great value in understanding the efflux process and in the future design of new fluoroquinolones with improved bioavailability. As inhibitors two well known Pgp inhibitors, cyclosporine (cA) and verapamil (V), and a mixed inhibitor of Pgp and the organic cation transporter OCT1, quinidine (Q), and a well established MRP substrate, p-aminohipuric acid (pA), have been selected, in order to point out the possible carriers implicated.
Section snippets
Compounds assayed
Ciprofloxacin (CIP) and Sparfloxacin (SPX) were kindly donated by CENAVISA (Reus, Spain), Grepafloxacin hydrochloride (GRX) was given by Glaxo–Wellcome (United Kingdom). Verapamil hydrochloride (V), p-aminohipuric acid (pA), quinidine (Q) and cyclosporine-A (cA) were purchased from Sigma (Barcelona, Spain).
In situ absorption studies
The study was approved by the Scientific Committee of Animal Use of the Faculty of Pharmacy and follows the guidelines described in the EC Directive 86/609, the Council of the Europe
Ciprofloxacin studies
Permeability values of CIP in the different situations assayed are listed in Table 1. As demonstrated in a previous work [16], if CIP is perfused in situ at 1.5 μM, the simultaneous presence of V produces a significant increase in the permeability, implying that there is a significant contribution of the secretion by Pgp. Nevertheless, as can be observed in Table 1, increasing CIP concentration to 50 μM results in a lack of inhibitor effect. Even higher concentrations of V (2 mM, 20 times the
Acknowledgements
This work represents a part of the Project GV 99-99-1-12, granted by the Conselleria de Cultura, Educación y Ciencia de la Generalitat Valenciana. The authors are also indebted to the Spanish Ministry of Education and Science for RN's grant. Thanks are given to Ms Miriam Phillips for the English revision of the text.
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Department of Biotechnology, Politechnic University of Valencia, Spain.