Pharmakokinetik des Pentoximesters

The development of prodrugs aims at the formation of rather lipophilic compounds, which exhibit enhanced oral bioavailability and are activated by physiological enzymes after absorption. The bioactivation of pentoximeester, a double prodrug of pentamidine, could be demonstrated in particular by microsomal and mitochondrial enzymes, present in several organs. Additionally, oral absorption of the pentoximeester, its activation to pentamidine and distribution were determined by in vivo studies in pigs. Although neither pentamidine nor other metabolic intermediates were detected in plasma, oral bioavailability of the prodrug and biotransformation to the active drug could be confirmed. Pentamidine was found to accumulate in metabolising tissues such as kidney or liver. With respect to physico-chemical characterisation, lipophilicity, pka values, polar surface area and number of H-bond donors or acceptors were determined. The pentoximeester exhibits an increased lipophilicity in comparison to pentamidine, allowing its transport across the mucosal membrane by passive diffusion. Taking potential drug-drug interactions into consideration, in vitro studies were performed. Protein binding and interactions with distinct cytochrome P450 isoenzymes were investigated. No significant interactions could be related to the pentoximeester and pentamidine.

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