Dr. Fromm showed that increased plasma concentrations of a pharmaceutical can be caused by the inhibition of the transporter protein P-glycoprotein when simultaneously administering a second drug.

Some patients simultaneously receive quinidine, a drug for the treatment of cardiac dysrhythmia, and digoxin, which strengthens the contractive power of the cardiac muscle in patients suffering from cardiac insufficiency. When ingesting quinidine, fixed doses of digoxin lead to higher plasma concentrations of digoxin, thereby presenting the risk of an overdose. It is known that digoxin is excreted without a significant degree of degradation with the help of P-glycoprotein, which occurs e.g. in the kidneys, the liver and the intestines. It is a transporter protein that aids mainly in the elimination of chemotherapy drugs but also of a large number of other pharmaceuticals.

The award winner examined the hypothesis that P-glycoprotein-mediated digoxin elimination is inhibited by quinidine, which would explain the known increase of the digoxin concentration for the simultaneous administration of quinidine.

Dr. Fromm was able to show the active transcellular transport of digoxin and quinidine in cell cultures, as long as P-glycoprotein was present in the cell lines in polarized form. This digoxin transport could be inhibited through quinidine. He made another successful observation with so-called knock-out mice, from whom the gene for the digoxin-transporting P-glycoprotein had been removed.

While quinidine triggered the expected increase in the plasma concentrations of digoxin in the control group, this effect was no longer observed in the knock-out mice. In summary, quinidine and digoxin compete as substrates for the transport through P-glycoprotein. It was shown that the inhibition of a transporter protein may represent a drug interaction that leads to an increased pharmaceutical concentration.

The paper honored with the Paul Martini Prize was published in 1999 in Circulation, the scientifically most reputable cardiology journal. This research project addressed an issue with immediate clinical relevance and the most sophisticated methods for a specific contribution to the improvement of pharmaceutical safety. In a subsequent paper, Dr. Fromm has examined the importance of the so-called prehepatic drug metabolism in the mucous membrane of the small intestine (i.e. before the liver passage).

When several pharmaceuticals are administered orally at the same time, the intestinal metabolism in humans can proceed more quickly and result in an undesirable loss of efficacy for one of the drugs. Overall, the author is credited with having shifted the focus of attention in both clinical pharmacology and pharmacogenetics to the prehepatic metabolism.