Stereoselective glucuronidation of formoterol by human liver microsomes

Aims Formoterol is a beta(2)-adrenoceptor agonist marketed as a racemic mix ture of the active (R; R)- and inactive (S; S)-enantiomers (rac-formoterol) . The drug produces prolonged bronchodilation by inhalation but there is si gnificant interpatient variability in duration of effect. previous work has shown that in humans formoterol is metabolized by conjugation with glucuro nic acid but little is known about the stereoselectivity of this reaction. The aim of the present study was to investigate the glucuronidation of form oterol enantiomers in vitro, by human liver microsomes. Methods The kinetics of formation of formoterol glucuronides during incubat ion of racemate and of single formoterol enantiomers with human liver micro somes (n=9) was characterized by chiral h.p.l.c. assay. Results The kinetics of glucuronidation of the two formoterol enantiomers o beyed the Michaelis-Menten equation. Glucuronidation of formoterol was ster eoselective and occurred more than two times faster for (S; S)-formoterol t han for (R; R)-formoterol. In incubations with single formoterol enantiomer s, the median (n=9) K-m values for (R; R)-glucuronide and (S; S)-glucuronid e were 827.6 and 840.4 mu M, respectively, and the median V-max values were 2625 and 4304 pmol min(-1) mg(-1), respectively. Corresponding values dete rmined in incubations with rac-formoterol were 357.2 and 312.1 mu M and 143 5 and 2086 pmol min(-1) mg(-1) for (R; R)- and (S; S)-glucuronide, respecti vely. Interindividual variation was large with the ratio of V-max/K-m (S; S /R; R) ranging from 0.57 to 6.90 for incubations with rac-formoterol. Conclusions Our study demonstrates that glucuronidation of formoterol by hu man liver microsomes is stereoselective and subject to high interindividual variability. These findings suggest that clearance of formoterol in humans is subject to variable stereoselectivity which could explain the variation in duration of bronchodilation produced by inhaled formoterol in patients with asthma.