Evaluation of Prokinetic Action of Clarithromycin using Orocecal Transit Time in Healthy Human Subjects

摘要

Clarithromycin is a synthetic analogue of Erythromycin and shares its prokinetic action to various extents. The objective of this study is to investigate the prokinetic action of clarithromycin by a non-invasive and reproducible technique compared against placebo and loperamide. The randomized, open, placebo-controlled, crossover study in healthy human subjects approved by Institutional Ethics Committee. Eleven healthy male volunteers were enrolled in the study. The subjects were given placebo or 2mg loperamide or 500mg clarithromycin and crossover was done after a seven day washout period. Orocecal transit time was evaluated by measuring saliva sulfapyridine appearance time after the administration of sulfasalazine. Mean salivary sulfapyridine lag time with placebo was 313.64 ± 49.05 minutes, with loperamide >480 minutes and with clarithromycin 245.45 ± 56.63 minutes. As compared to placebo and loperamide, sulfapyridine lag time with clarithromycin was significantly reduced (p<0.001). The results indicate the prokinetic effect of clarithromycin similar to erythromycin. Introduction Macrolide antibiotics like erythromycin and clarithromycin are widely used in the clinical practice for various infections including Helicobacter pylori eradication. 1 Clarithromycin is more acid-stable than erythromycin and is rapidly absorbed after oral administration with a bioavailability of about 55%. Clarithromycin is a well tolerated antibiotic; the frequency of gastrointestinal side effects is much lower than with erythromycin. Oral erythromycin and its analogues have been shown to significantly increase gastrointestinal motility by acting on motilin receptors. 2 Endogenous agonist of these receptors is motilin. Motilin is 22-aminoacid peptide found in gastrointestinal M cells, some enterochromaffin cells and proximal small intestine. 3,4 Motilin, erythromycin and other motilides show prokinetic action mainly by acting on motilin receptor and causing prolonged depolarization in a subset of neurons 4,5 and to certain extent through the release of acetylcholine from intrinsic cholinergic neurons and by direct muscular action. 6 Motilin receptor (Fig.1) is a G protein-coupled receptor whose loop and the tail regions are quite varied and provide the diversity of themes allowing the binding of structurally diverse ligands. 7 Motilin binds with the residues at the membrane interface at each end of the long loop [Val 179 , Leu 245 , Arg 246 ] and the residues at the amino-terminal tail and extracellular loop domains [Gly 36 , Pro 103 , Leu 109 and Phe 332 ]. 7 Erythromycin and other non-peptidyl motilin receptor agonists bind to intramembranous regions of the receptor. The intradomain disulfide bond between two cysteine residues [Cys 25 and Cys 30 ] within the amino-terminal tail domain is shown to have functional significance for both motilin and erythromycin action. 8