Salmeterol is an inhaled long-acting selective beta(2)-adrenoceptor agonist that is commercially available as the xinafoate (1-hydroxy-2-naphthoic acid) salt of the racemic mixture of the two optical isomers, (R)- and (S)-, of salmeterol. It acts locally in the lung through action on beta2 receptors. Limited data have been published on the pharmacokinetics of salmeterol. Moreover, there are no data on the extent to which inhaled salmeterol undergoes first-pass metabolism. This lack of information is most likely due to the very low plasma concentrations reached after inhalation of therapeutic doses of salmeterol and the problems in developing an analytical method that is sensitive enough to determine these concentrations. When salmeterol is inhaled, plasma concentrations of the drug often cannot be detected, even at 30 minutes after administration of therapeutic doses. Larger inhaled doses give approximately proportionally increased blood concentrations. Plasma salmeterol concentrations of 0.1 to 0.2 and 1 to 2 microg/L have been attained in healthy volunteers about 5 to 15 minutes after inhalation of a single dose of 50 and 400 microg, respectively. In patients who inhaled salmeterol 50microg twice daily for 10 months, a second peak concentration of 0.07 to 0.2 microg/L occurred 45 to 90 minutes after inhalation, probably because of the gastrointestinal absorption of the swallowed drug. Salmeterol xinafoate dissociates in solution to salmeterol and 1-hydroxy-2-naphthoic acid. These two compounds are then absorbed, distributed, metabolised and excreted independently. The xinafoate moiety has no apparent pharmacological activity, is highly protein bound (>99%), largely to albumin, and has a long elimination half-life of about 12 to 15 days in healthy individuals. For this reason, it accumulates in plasma during repeated administration, with steady-state concentrations reaching about 80 to 90 microg/L in patients treated with salmeterol 50microg twice daily for several months. The cytochrome P450 (CYP) isoform 3A4 is responsible for aliphatic oxidation of salmeterol base, which is extensively metabolised by hydroxylation with the major metabolite being alpha-hydroxysalmeterol, with subsequent elimination predominantly in the faeces. It has been demonstrated that 57.4% of administered radioactivity is recovered in the faeces and 23% in the urine; most is recovered between 24 and 72 hours after administration. Unchanged salmeterol accounts for <5% of the excreted dose in the urine. Since the therapeutic dose of salmeterol is very low, it is unlikely that any clinically relevant interactions will be observed as a consequence of the coadministration of salmeterol and other drugs, such as fluticasone propionate, that are metabolised by CYP3A. All the available data clearly show that at the recommended doses of salmeterol, systemic concentrations are low or even undetectable. This is an important point, because it has been demonstrated that the systemic effects of salmeterol are more likely to occur with higher doses, which lead to approximately proportionally increased blood concentrations.