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Abstract The unpredictable oral bioavailability of established drugs like tacrolimus and sulfasalazine presents a significant clinical challenge. This variability can lead to either toxicity or insufficient therapeutic effect. It is known that alterations in drug transporters and metabolic enzymes influence drug bioavailability. Recent evidence suggests that the indirect metabolism by gut microbes could influence transporters and enzymes which can affect the bioavailability of oral drugs. In this study, the pharmacokinetics of tacrolimus and sulfasalazine are modeled under varying host colonic conditions induced by the bacteriaE. coli Nissle 1917andBifidobacterium adolescentis. Insight is provided into the sensitivity of pharmacokinetics to the bacterial influence on expression of intestinal drug transporters and cytochrome p450 enzymes. Our findings demonstrate that bacterial modulation reduces tacrolimus peak blood concentration compared to healthy renal transplant patients. Conversely, bacterial presence leads to a two‐fold increase in sulfasalazine's peak plasma concentration compared to healthy subjects. These results suggest that incorporating the gut bacteria's influence on colonic transporters and enzymes can improve the explanation of pharmacokinetic variability. This approach has the potential to refine pharmacokinetic models and ultimately address the challenge of variable oral drug bioavailability.