|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service.. M Jerling; L Lindstr÷m; U Bondesson; L Bertilsson (1994) Therapeutic drug monitoring display abstract
Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.. S E Ball; D Ahern; J Scatina; J Kao (1997) British journal of clinical pharmacology display abstract
AIMS: In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2). METHODS: Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). RESULTS: Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. CONCLUSIONS: It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.
Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.. A D Kashuba; A N Nafziger; G L Kearns; J S Leeder; R Gotschall; M L RocciJr; R W Kulawy; D J Beck; J S BertinoJr (1998) Clinical pharmacology and therapeutics display abstract
OBJECTIVE: To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam. METHODS: Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity. RESULTS: No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively. CONCLUSIONS: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.