In vivo Pharmacokinetics of Two New Thrombin Inhibitor Prodrugs : Emphasis on Intestinal and Hepatobiliary Disposition and the Influence of Interacting Drugs
Abstract: Biliary excretion is an important elimination route for many drugs and metabolites. For such compounds, it is important to know the extent of excretion and drug exposure in the bile, e.g., for the risk assessment of drug interactions, liver toxicity and the effects of genetic variants. In this thesis, duodenal aspiration of bile was performed in healthy volunteers and complemented with experiments in an in vivo model in pigs to increase the understanding of the intestinal and hepatobiliary disposition of two direct thrombin inhibitors.The compounds investigated, ximelagatran and AZD0837, are both prodrugs that require bioactivation to exert their pharmacological effect. Upon co-administration with erythromycin and ketoconazole, respectively, altered plasma exposure to ximelagatran and AZD0837 and their respective metabolites has been observed. The main objective of this thesis was to characterize the biliary excretion of the compounds, and investigate whether this elimination route explains the observed drug-drug interactions.High plasma-to-bile AUC ratios were observed, in particular for ximelagatran, its active metabolite melagatran, and AR-H067637, the active metabolite of AZD0837. These high ratios indicate the involvement of active transporters in the biliary excretion of the compounds, which is important since transporters constitute possible sites for drug interactions. The effects of erythromycin and ketoconazole on the plasma exposure of the prodrugs and metabolites were confirmed in both the pig and the clinical studies. The changes seen in plasma for ximelagatran and its metabolites were partly explained by reduced biliary clearance. Inhibited CYP3A4 metabolism likely caused the elevated plasma levels of AZD0837, whereas reduced biliary clearance was seen for AR-H067637 suggesting an effect on its excretion into bile. In summary, the studies led to mechanistic insights in the hepatobiliary disposition of ximelagatran and AZD0837, and demonstrate the value of combined clinical and animal studies for the investigation of the biliary drug excretion.
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