Pharmakatransport im Atemwegsepithel

H. B. Paul; T. Welte; D. A. Groneberg

doi:10.1055/s-2004-870942

Pneumologie, Table of Contents

Pneumologie 2005; 59(7): 461-469
DOI: 10.1055/s-2004-870942

Übersicht

Pharmakatransport im Atemwegsepithel

Drug Transport in the Respiratory EpitheliumH. B. Paul^1, ² , T. Welte² , D. A. Groneberg^1, ²

¹Abteilung für Pneumologie, Medizinische Hochschule Hannover, (Leiter: Prof. Dr. T. Welte)
²Klinische Forschergruppe Allergologie, Charité-Universitätsmedizin Berlin, Freie Universität Berlin und Humboldt-Universität zu Berlin, (Leiter: Prof. Dr. A. Fischer)

Abstract

Zusammenfassung

Die aerosolische Administration von Peptidomimetika könnte in der Zukunft bei der Behandlung einer Vielzahl pulmonaler und systemischer Erkrankungen eine wichtige Rolle spielen. Insbesondere ergeben sich durch die neuen Verfahren der rationalen Substanzentwicklung Möglichkeiten, spezifische Pharmaka zu entwerfen, die durch Transportproteine effizient durch das Epithel transportiert werden. Von den zwei derzeitig bekannten Pharmakatransportern PEPT1 und PEPT2, die aus menschlichem Gewebe kloniert worden sind, konnte der hochaffine PEPT2-Transporter in der Lunge nachgewiesen werden. Es handelt sich um ein Membranprotein mit 12 transmembranären Domänen, welches durch Kopplung an einen zelleinwärts gerichteten elektrochemischen Protonengradienten Substrate transportiert. In den menschlichen Atemwegen konnte die Expression von PEPT2 im Bronchialepithel und in Pneumozyten Typ 2 gefunden werden. Aufnahmestudien zeigen, dass sowohl Peptide sowie auch Peptidomimetika wie Antibiotika, antivirale Substanzen und Zytostatika durch PEPT2 transportiert werden. PEPT2 ist ebenso verantwortlich für den Transport der Delta-Aminolävulinsäure, die in der photodynamischen Therapie und Diagnostik von pulmonalen Neoplasien verwendet wird. Ausgehend von neuesten Erkenntnissen im Bereich Substratbindung- und -Transport rückt PEPT2 als Transportsystem zukünftiger, mittels rationaler Substanzentwicklung generierter Atemwegstherapeutika und Prodrugs in das Blickfeld therapeutischer Überlegungen.

Abstract

The aerosolic administration of peptidomimetic drugs with a peptide backbone may play a crucial role in the future treatment of diseases. Especially rational drug design offers an option to synthesize new drugs that are carried by specific drug transporters. Out of the presently identified transporter proteins PEPT1 and PEPT2, the high-affinity transporter PEPT2 is found in the respiratory tract. The transporter possess 12 membrane spanning domains and catalyses an electrogenic uphill drug transport using a transmembrane electrochemical proton gradient. PEPT2 is expressed in the bronchial epithelium and in alveolar type II pneumocytes in human airways. Kinetic studies demonstrated that peptidomimetic compounds including antibiotic, antiviral and antineoplastic drugs are carried by PEPT2. The transporter also carries delta-aminolevulinic acid into the airways. This molecule can be used for the diagnostics of pulmonary neoplasms and for photodynamic therapy. Using the recently published data on minimal structural requirements for PEPT2-substrates, rational drug design may lead to a new generation of respiratory drugs and prodrugs, which are delivered to the airways via the molecular mechanisms of the PEPT2 transport system.

Full Text

References

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Priv.-Doz. Dr. med. David A. Groneberg

Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin · Freie Universität Berlin und Humboldt-Universität zu Berlin

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Email: david.groneberg@charite.de