Research paper
Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies

https://doi.org/10.1016/S0939-6411(02)00185-6Get rights and content

Abstract

The influence of the secretion process on the absorption of ciprofloxacin, grepafloxacin and sparfloxacin has been evaluated by means of inhibition studies. Two well known P-glycoprotein inhibitors (cyclosporine, verapamil), a mixed inhibitor of P-glycoprotein and the organic cation transporter OCT1 (quinidine) and a well established MRP substrate (p-aminohipuric acid) have been selected in order to distinguish the possible carriers implicated. An in situ rat gut perfusion model and CACO-2 permeability studies are used. Both methods suggest the involvement of several types of efflux transporters for every fluoroquinolone. The relevance of the secretory pathway depends on the intrinsic permeability of the quinolone. The in vitro model seems to be more suitable for discriminating mechanisms underlying the absorption process, while in situ studies are less sensitive to 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.

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