SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND THEOPHYLLINE METABOLISM IN HUMAN LIVER-MICROSOMES - POTENT INHIBITION BY FLUVOXAMINE

1 Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2 None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only potent inhibitor of CYP3A having IC50 values of 11 mu M and 19 mu M for testosterone 6 beta-hydroxylase and cortisol 6 beta-hydroxylase, respectively. 3 Norfluoxetine, sertraline and fluvoxamine inhibited CYP1A1 (7-ethoxyresorufin O-deethylase) in microsomes from human placenta (IC50 values 29 mu M, 35 mu M and 80 mu M, respectively). Fluvoxamine was a potent inhibitor of CYP1A2-mediated 7-ethoxyresorufin O-deethylase activity (IC50 = 0.3 mu M) in human liver. 4 In microsomes from three human livers fluvoxamine potently inhibited all pathways of theophylline biotransformation, the apparent inhibitor constant, K-i, was 0.07-0.13 mu M, 0.05-0.10 mu M and 0.16-0.29 mu M for inhibition of l-methylxanthine, 3-methylxanthine and 1,3-dimethyluric acid formation, respectively Seven other SSRIs showed either weak or no inhibition of theophylline metabolism. 5 Ethanol inhibited the formation of 1,3-dimethyluric acid with a K-i value of 300 mu M, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6 It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.