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Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells.

Ergotamine (2′-methyl-5′α-benzyl-12′-hydroxy-3′,6′,18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus Claviceps purpurea. Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT[sub.1]-serotonin receptors. Based on the structural formula of ergotamine, we hypothesized that ergotamine might stimulate 5-HT[sub.4]-serotonin receptors or H[sub.2]-histamine receptors in the human heart. We observed that ergotamine exerted concentration- and time-dependent positive inotropic effects in isolated left atrial preparations in H[sub.2]-TG (mouse which exhibits cardiac-specific overexpression of the human H[sub.2]-histamine receptor). Similarly, ergotamine increased force of contraction in left atrial preparations from 5-HT[sub.4]-TG (mouse which exhibits cardiac-specific overexpression of the human 5-HT[sub.4]-serotonin receptor). An amount of 10 µM ergotamine increased the left ventricular force of contraction in isolated retrogradely perfused spontaneously beating heart preparations of both 5-HT[sub.4]-TG and H[sub.2]-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergotamine 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, that were attenuated by 10 µM of the H[sub.2]-histamine receptor antagonist cimetidine, but not by 10 µM of the 5-HT[sub.4]-serotonin receptor antagonist tropisetron. These data suggest that ergotamine is in principle an agonist at human 5-HT[sub.4]-serotonin receptors as well at human H[sub.2]-histamine receptors. Ergotamine acts as an agonist on H[sub.2]-histamine receptors in the human atrium.