Measurement of unbound ranitidine in blood and bile of anesthetized rats using microdialysis coupled to liquid chromatography and its pharmacokinetic application
Introduction
Ranitidine {N-(3-[{[5-(dimethylamine)methyl-2-furanyl]methyl}thio]ethyl)-N9-methyl-2-nitro-1,1-ethenediamine hydrochloride} is the H2-receptor antagonist used for peptic ulcer [1]. Analysis of ranitidine from biological samples is commonly performed using high-performance liquid chromatography (HPLC) coupled to UV detection [2], [3] and tandem mass spectrometry [4], [5]. Sample preparation of ranitidine from human plasma has been accomplished by deproteination using perchloric acid [3] and solid-phase extraction [5], [6]. On the whole, these methods are time-consuming, and require tedious procedures for the preparation of biological samples. However, only protein-unbound drugs are available for drug distribution to the target site and for therapeutic application. To date, measurement of protein-unbound ranitidine in the blood and bile has not been described. Microdialysis technique provides an in vivo method to monitor unbound drug in various biological fluids, which excludes large molecule out of the dialysis membrane [7].
Since ranitidine interacts with the P-glycoprotein (P-gp), clarification of the transport mechanism may provide important information for studying the pharmacokinetics of ranitidine. It is also to be noted that not all P-glycoprotein substrates are subject to significant biliary excretion. Thus, to obtain more detailed information about the disposition of ranitidine in vivo, this study investigates the pharmacokinetics of unbound ranitidine in rat blood and bile using a microdialysis sampling technique coupled with HPLC. In addition, further exploration of the mechanism concerning the hepatobiliary excretion of ranitidine is also observed by comparing the pharmacokinetics of ranitidine present both with and without cyclosporine, a P-gp inhibitor, and quinidine, an OCT inhibitor, subsequently.
Section snippets
Chemicals and reagents
Ranitidine was purchased from Aldrich (Milwaukee, WI, USA). Cyclosporine (Sandimmun) and quinidine were obtained from Novartis Pharma (Basle, Switzerland) and Sigma (St. Louis, MO, USA), respectively. Triply deionized water from Millipore (Bedford, MA, USA) was used for all preparations.
Animal experimentation
All experimental protocols involving animals were reviewed and approved by the institutional animal experimentation committee of the National Research Institute of Chinese Medicine. Male specific pathogen-free
Results and discussion
The present validated liquid chromatographic method was coupled to the microdialysis technique and employed to determine ranitidine disposition from rat jugular vein blood and bile following drug administration. The method demonstrated excellent chromatographic selectivity with no endogenous interferences at the peak for ranitidine. Retention time of ranitidine was about 6.5 min. The mobile phase contains 5% acetonitrile and 95% phosphate buffer, ranitidine was not separated well from biological
Acknowledgement
This study was supported in part by research grants (NSC93-2113-M-077-005; NSC93-2320-B-077-006) from the National Science Council, Taiwan.
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