Gr. Manchee et al., THE ALIPHATIC OXIDATION OF SALMETEROL TO ALPHA-HYDROXYSALMETEROL IN HUMAN LIVER-MICROSOMES IS CATALYZED BY CYP3A, Drug metabolism and disposition, 24(5), 1996, pp. 555-559
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.