THE ALIPHATIC OXIDATION OF SALMETEROL TO ALPHA-HYDROXYSALMETEROL IN HUMAN LIVER-MICROSOMES IS CATALYZED BY CYP3A

Salmeterol xinafoate (Serevent) is a long-acting beta(2)-adrenoceptor agonist, used in the treatment of asthma, that has bronchodilator and anti-inflammatory action. Salmeterol is extensively metabolized by ali phatic oxidation in humans, with the major metabolite being alpha-hydr oxysalmeterol. The aim of this investigation was to identify the speci fic cytochrome P450 (P450) isoform or isoforms involved in the formati on of alpha-hydroxysalmeterol in human liver microsomes. [C-14]Salmete rol was incubated with a pooled sample (N = 19) of human liver microso mes in the absence or presence of selective chemical inhibitors of the major human P450 isoforms. One mu M ketoconazole, a selective inhibit or of CYP3A, substantially inhibited the metabolism of salmeterol to a lpha-hydroxysalmeterol. Disulfiram caused a small but consistent decre ase in the amount of alpha-hydroxysalmeterol formed, possibly reflecti ng less than total selectivity for CYP2E1 under the conditions used. O ther selective inhibitors had no significant effect on the metabolism of salmeterol. The rates of formation of alpha-hydroxysalmeterol in 10 individual liver microsomal samples showed an approximately 10-fold v ariation and were found to be highly correlated (r(2) = 0.94; p <0.001 ) with rates of metabolism of midazolam to 1'-hydroxymidazolam, a mark er of CYP3A activity, in the same microsomal samples, No significant c orrelation was evident for the metabolism of salmeterol with levels of total P450 or other markers of human P450 activities in the same micr osomal samples, thus indicating that the formation of alpha-hydroxysal meterol is catalyzed predominantly by CYP3A, Insect cell microsomes th at coexpressed human CYP3A and NADPH-P450 reductase were able to metab olize [C-14]salmeterol to alpha-hydroxysalmeterol, thus confirming the role of CYP3A in catalyzing this reaction, The therapeutic dose of sa lmeterol is very low, so it is unlikely that any clinically relevant i nteractions will be observed as a consequence of the coadministration of salmeterol and other pharmaceutical agents that are metabolized by CYP3A.