Effect of Antibiotics on the Metabolism and Pharmacokinetics of Amlodipine and Aspirin

Abstract

Xenobiotic metabolism involves the biochemical modification of drugs that normally occur mainly in the liver. Most xenobiotic metabolic processes in the liver convert hydrophobic compounds into hydrophilic products and thereby facilitate excretion and detoxification. The gut microbiota plays an important role in drug metabolism through secretion of microbial drug-metabolizing enzymes. The gastrointestinal microbiota is involved in reductive and hydrolytic reactions generating hydrophobic products. In this study, we investigated the effects of antibiotics on the metabolism and pharmacokinetics of amlodipine and aspirin by using fecalse metabolism in vitro, and its application to pharmacokinetic study. In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. When aspirin was anaerobically incubated with human and rat fecal microbiota, aspirin was metabolized to yield two metabolites salicylic acid (major metabolite) and hydroxyl salicylic acid. Oral administration of ampicillin significantly reduced gut microbial drug-metabolizing enzyme activity in rats. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls, the active metabolite of aspirin, salicylic acid, was significantly higher in ampicillin-treated rats, as compared with control rats In pharmacodynamic perspective view, the anti-platelet activity test using tail bleeding assay was investigated, ampicillin treatment significant prolonged the bleeding time in aspirin-dosed rats. These findings suggest that co-administration of antibiotics may affect the metabolism and pharmacokinetics of amlodipine and aspirin via the modulation of metabolic activity of gut microbiota, which could further influence the therapeutic potency of drugs.