The intestinal absorption characteristics and the efflux mechanisms of zolmitriptan, a new generation and highly selective 5-HT(1B/1D) receptor agonist used in the acute oral treatment of migraine, were investigated. A human intestinal cell line, Caco-2, was used as an in-vitro model of the intestinal mucosa to assess transepithelial transport of zolmitriptan. In the Caco-2 cells, the absorptive transport of zolmitriptan was pH dependent and the transport was enhanced at weakly alkali pH on the apical side. No concentration dependence and saturation were observed for the apical-to-basolateral and basolateral-to-apical transport of zolmitriptan at a concentration of 0.1-10 mM. The permeability ratio value was about 1.5-2.6 at a concentration of 0.1-2.0 mM. Inhibition experiments using verapamil, nifedipine and nimodipine as inhibitors were studied and indicated that P-glycoprotein participated in the transport of zolmitriptan. Inhibition of the Na+-H+ exchanger with amiloride resulted in a significant increase in absorption and a slight inhibition in secretion. This suggests that the Na+-H+ exchanger may be involved in the transport of zolmitriptan. The results indicated that the transport of zolmitriptan was mediated by both passive diffusion and active transport. A series of drug-drug interaction experiments were carried out between zolmitriptan and some drugs that may be co-administrated with zolmitriptan in the clinic. The results indicated that flunarizine, cetirizine, propranolol and atenolol potently decreased both the apical-to-basolateral and basolateral-to-apical transport rate of zolmitriptan. Cimetidine and aspirin slightly inhibited the apical-to-basolateral transport of zolmitriptan, but significantly decreased the basolateral-to-apical transport of zolmitriptan. Thus, the absorption drug-drug interactions should be considered when these drugs are co-administrated with zolmitriptan in the clinic.