Factors affecting solubility and penetration of clarithromycin through gastric mucus.

Abstract

Factors influencing the pharmacokinetics of clarithromycin in gastric mucus are poorly defined. To determine: (i) whether the clinical formulation of clarithromycin (Biaxin granules and powdered Biaxin tablets) affects the water solvency of the antibiotic or changes the barrier properties of pig gastric mucus (PGM), thereby influencing the penetration of clarithromycin through the gastric mucus layer; and (ii) whether topically active anti-ulcer agents affect clarithromycin penetration through gastric mucus. Solubility of clarithromycin in aqueous solution was studied at pH 7. PGM viscosities were determined using a falling ball microviscometer. Permeability of clarithromycin through PGM with and without added anti-ulcer drugs at pH 7 was monitored using a microfiltration device and an agar diffusion bioassay. Clarithromycin showed the poorest solubility at pH 7, whereas both Biaxin formulations demonstrated identical solubility of their antibiotic ingredient. Clarithromycin and both Biaxin formulations markedly increased mucin viscosity over the pH range 2-7. PGM markedly retarded the penetration of clarithromycin: unformulated clarithromycin and Biaxin tablets penetrated more rapidly through mucus than Biaxin granules. Pre-treatment of PGM with aluminium-magnesium-containing antacids (Riopan and Talcid preparations) decreased the rate of clarithromycin penetration, whereas Carafate and Peptobismol had no significant effect on mucus penetration of clarithromycin. The availability of clarithromycin in gastric mucus is significantly influenced by its clinical formulation, which affects its solubility as well as the viscous properties of mucus. Pulverized Biaxin tablets provide better local distribution of clarithromycin in mucus than Biaxin granules. Pre-treatment of mucus with anti-ulcer medications does not increase the penetration of clarithromycin through mucus.