New findings on melatonin absorption and alterations by pharmaceutical excipients using the Ussing chamber technique with mounted rat gastrointestinal segments
Introduction
Melatonin is an indoleamide hormone that is endogenously secreted by the pineal gland in the brain according to a day–night cycle (Lee et al., 1999). Melatonin acts as a circadian rhythm synchronizer and endogenous antioxidant (Pandi et al., 2006). Oral melatonin preparations are important since exogenous administration of melatonin can be clinically used to maintain/initiate sleep and treat circadian rhythm disorders (Lee et al., 1999). However, the bioavailability of orally administered melatonin preparations in human subjects is limited and variable (Lee et al., 1995). Melatonin is slightly soluble, has good permeability characteristics, and is in the class II category according to the Biopharmaceutics Classification System (Lee et al., 1997, Vlachou et al., 2006). Although the physical properties and numerous oral dosage forms of melatonin have been studied, an understanding of melatonin absorption is very limited. No information about the GI absorption of melatonin and its p-glycoprotein (P-gp) dependency is available.
Drug absorption is a key process governing the in vivo bioavailability of drugs. It is affected by the physicochemical properties of the drug, dosage form, biological state of the gastrointestinal (GI) tract, and co-administered food components (Lee et al., 1997, Wagner et al., 2001). In particular, pharmaceutical excipients can significantly modify physicochemical properties, intestinal permeability, and drug bioavailability when co-administered with a drug (Mithani et al., 1996, Vine et al., 2002, Sharma et al., 2005). Bile acids and fatty acids are generally recognized as safe (GRAS)-listed pharmaceutical excipients and are common components in food and dosage formulations. These excipients have been widely studied as absorption promoters and inhibitors of various drugs. Formation of stable micellar structure could explain changing drug absorption (Yamaguchi et al., 1986b, Sharma et al., 2005). However, no information on the potential modulation of melatonin absorption by these pharmaceutical excipients is available.
The aim of this work was to understand the in vitro absorption behaviors and P-glycoprotein dependency of melatonin using the Ussing chamber technique with mounted rat GI segments. The modulation of melatonin absorption by GRAS-listed sodium cholate and sodium oleate at different concentration levels was also examined.
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Materials
Melatonin was purchased from Morepen (New Delhi, India). Absolute alcohol (99.9%) was purchased from Hayman (Witham, England). Sodium oleate, sodium cholate, and sodium chloride were purchased from Sigma (St. Louis, MO, USA). The saline solution (0.9% NaCl) was purchased from Choongwae Pharm. Inc. (Seoul, Korea). Lucifer yellow, Kreb's Ringer bicarbonate buffer and rhodamine 123 were purchased from Sigma–Aldrich (Seoul, Korea). Deionized water was used throughout the study. All other chemicals
Site dependence of melatonin absorption behavior
The site dependency of melatonin absorption through excised rat GI segments at 0.01% melatonin is given in Fig. 1. Melatonin was continuously absorbed and the absorption rate increased as a function of time. The cumulative absorption of a dose of 0.01% (100 μg/mL) melatonin in excised segments of the duodenum, jejunum and colon was similar at about 65.5 ± 3.4 ng/mL after 90 min. The cumulative absorption was the highest in the rectum (157.4 ± 20 ng/mL) followed by the ileum (104.8 ± 5.2 ng/mL) and three
Conclusions
Melatonin absorption occurs throughout the GI tract but shows absorption site dependency. The extent of absorption was highest in the rectum followed by the ileum. However, the absorption behaviors of melatonin are more complicated when simultaneously dosed with excipients. Melatonin absorption varied by the concentration of excipient. Tissue damage, formation of micellar complexes as characterized by 1H NMR analysis, and particle size distribution could affect the melatonin absorption rate.
Acknowledgements
This work was supported by the Korea Science and Engineering Foundation (KOSEF: R01-2008-000-11777-0). We also thank the Central Research Laboratory for the use of the NMR and dynamic light scattering and the Research Institute of Pharmaceutical Sciences, Kangwon National University for allowing the use of their HPLC systems. We would like to thank Dr. Seung Koo Lee for help in examining the histological tests.
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