Rolle von nukleären Rezeptoren beim hepatischen und intestinalen Medikamententransport[1]

Zusammenfassung

Die Bioverfügbarkeit von Medikamenten wird wesentlich durch die intestinale Resorption und den hepatischen „first-pass”-Effekt determiniert. Hierbei muss die betreffende Substanz mehrere Membranbarrieren überwinden, um in den systemischen Blutkreislauf zu gelangen. Dazu gehören die luminale (dem Darmlumen zugewandte) und die basolaterale (der Blutseite zugewandte) Membran der Darmepithelzelle. Diejenigen Substanzen, die einem hohen hepatischen „first-pass”-Effekt unterliegen, werden über die basolaterale (sinusoidale) Hepatozytenmembran aufgenommen, in der Leberzelle biotransformiert und über die kanalikuläre (apikale) Membran in die Galle ausgeschieden. Jede der genannten Membranbarrieren besitzt spezialisierte Transportproteine, die den Stofftransport über die Membran bewerkstelligen. Eines der am besten charakterisierten Transporter ist das P-Glykoprotein MDR1 („multidrug resistance gene product”, Gensymbol ABCB1). MDR1 vermittelt in der apikalen Membran von Enterozyten den Rücktransport von Xenobiotika in das Darmlumen, noch bevor sie das Pfortaderblut erreichen. Eine Zunahme der MDR1-Proteinmenge kann die Bioverfügbarkeit von Substanzen, die MDR1-Substrate darstellen, entsprechend reduzieren. Beispiele hierfür sind Digoxin, Ciclosporin und Paclitaxel. Viele Xenobiotika wie zum Beispiel Rifampicin, Phenobarbital, Statine und Johanniskraut sind in der Lage, die MDR1 Expression transkriptionell zu induzieren. Das MDR1-Gen bindet den nukleären Rezeptor PXR („pregnane X receptor”), der nach Aktivierung durch die genannten Liganden die Gentranskription steigert. Weitere durch PXR regulierte Gene sind das Cytochrom P450 3A4, der Digoxintransporter OATP2 so ok?(Slc21a5) der basolateralen Hepatozytenmembran und die Xenobiotika-Effluxpumpe MRP2 (ABCC2) der kanalikulären Hepatozytenmembran. PXR ist somit ein entscheidender „Xenosensor”, der je nach Xenobiotikum die entgiftenden Transport- und Enzymsysteme des Darms und der Leber aktivieren kann.

Summary

Major determinants of the bioavailability of drugs are the degree of intestinal absorption and hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation. These include the luminal (facing the intestine) and basolateral (facing the blood) membrane of intestinal epithelial cells. Substances that undergo first-pass metabolism are taken up across the basolateral (sinusoidal) hepatocyte membrane, biotransformed within hepatocytes and excreted across the canalicular (apical) membrane into bile. Each of these membrane barriers possesses an array of specialized transport proteins that mediate substrate transport across the membrane. One of the best characterized transporters is the P-glycoprotein MDR1 (multidrug resistance gene product, gene symbol ABCB1). MDR1 is expressed at the apical surface of enterocytes where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. An increase in MDR1 expression reduces the bioavailability of drugs that are MDR1 substrates. Examples include digoxin, cyclosporin A and paclitaxel. Numerous xenobiotics such as rifampin, phenobarbital, statins and St. John’s wort induce MDR1 transcriptionally. The MDR1 gene binds the nuclear receptor PXR (pregnane X receptor) that induces gene transcription following activation by these ligands. Other PXR regulated genes include cytochrome P450 3A4, the digoxin transporter Oatp2 (Slc21a5) of the basolateral and the xenobiotic efflux pump MRP2 (ABCC2) of the canalicular hepatocyte membrane. PXR is thus an important „xenosensor” that mediates drug induced activation of the detoxifying transport and enzyme systems in liver and intestine.

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1 Unterstützung: Schweizerischer Nationalfonds (632-062773)