Salmeterol pharmacokinetics and molecular data

Pharmacokinetics
Overview Absorption Distribution Metabolism Excretion Special populations Pharmacodynamics

Overview
Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and excreted independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Return to top

Absorption
Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (42 mcg of salmeterol inhalation aerosol twice daily). Following chronic administration of an inhaled dose of 42 mcg twice daily, salmeterol was detected in plasma within 5 to 10 minutes in 6 patients with asthma; plasma concentrations were very low, with peak concentrations of 150 pg/mL and no accumulation with repeated doses. Larger inhaled doses gave approximately proportionally increased blood levels. In these patients, a second peak concentration of 115 pg/mL occurred at about 45 minutes, probably due to absorption of the swallowed portion of the dose (most of the dose delivered by a metered-dose inhaler is swallowed). Return to top

Distribution
Binding of salmeterol to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher than those achieved following therapeutic doses of salmeterol. Return to top

Metabolism
Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base was detected in either urine or feces. Return to top

Excretion
In 2 healthy subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days. Return to top

Special populations
The pharmacokinetics of salmeterol base has not been studied in elderly patients or in patients with hepatic or renal impairment. Since salmeterol is predominantly cleared by hepatic metabolism, liver function impairment may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored. Return to top

Pharmacodynamics
Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in some patients produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium (see PRECAUTIONS). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). In 2 double-blind asthma studies, patients receiving either 42 mcg of salmeterol inhalation aerosol twice daily (N = 81) or 180 mcg of albuterol inhalation aerosol 4 times daily (N = 80) underwent continuous electrocardiographic monitoring during four 24-hour periods; no clinically significant dysrhythmias were noted. Continuous electrocardiographic monitoring was also performed in 2 double-blind studies in patients with chronic obstructive pulmonary disease. Return to top