Cytochrome CYP2D6 inhibitor

The effects of quinidine sulfate, 50 mg orally, an inhibitor of cytochrome CYP2D6, on the metabolism of dextromethorphan 50 mg have been studied in seven healthy volunteers in a randomized, double-blind, crossover, placebo-controlled study (24). Quinidine suppressed the conversion of dextromethorphan to dextrorphan in extensive metabolizers to the extent seen in poor metabolizers. The increased concentrations of dextromethorphan increased subjective and objective pain thresholds by 35 and 45 % respectively. This result suggests that debriso-quine/sparteine-type polymorphisms account for important differences in the effect of dextromethorphan and the balance between the analgesic effect of dextromethorphan and the hallucinogenic effect of dextrorphan. Concomitant use of quinidine or other inhibitors of CYP2D6 could... 

In EMs, inhibitors of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in PMs. Dosage adjustment of STRATTERA in EMs may be necessary when coadministered with CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine (see Dmg Interactions and PRECAUTIONS). In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine. 

Fluoxetine inhibits the activity of the cytochrome P450 isoenzyme CYP2D6 within the liver so that the metabolism of oxycodone to an aetive metabolite oxymorphone is reduced. The metabolism of hydroeodone and similar opioids may also be affected by CYP2D6 inhibitors, see Opioids Codeine and related drugs + Quinidine , p.l84. Buprenorphine and morphine are not metabolised by CYP2D6, so their metabolism would not be expeeted to be affected by fluoxetine. Buprenorphine is metabolised by CYP3A4 and so fluvoxamine might be expected to inhibit its metabolism to some extent. 

Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996 50(3) 209-215. 

Crewe HK, Lennard MS, Tucker GT, et al. The effect of selective serotonin reuptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992 34 262-265. 

Voorman RL, Maio SM, Hauer MJ, et al. Metabolism of delavirdine, a human immunodeficiency vims type-1 reverse transcriptase inhibitor, by microsomal cytochrome P450 in humans, rats, and other species probable involvement of CYP2D6 and CYP3A. Dmg Metab Dispos 1998 26(7) 63 l 639. 

Nitric oxide formed from amyl nitrite inhibits cytochrome P450 (117) and ritonavir inhibits CYP2D6 (118), which has a major role in metamfetamine detoxification (119). This interaction could have led to fatal plasma concentrations of metamfetamine. It is therefore suggested that patients who take protease inhibitors are made aware of the potential risk of using any form of recreational drugs metabolized by CYP2D6, particularly metamfetamine. 

An important consideration in the use of all HIV-1 protease inhibitors, but of ritonavir in particular, is their potential for drug interactions through their effects on cytochrome P450 isozymes. The various interactions of ritonavir with other antiretroviral drugs have been reviewed (139). Ritonavir, which inhibits CYP2D6, the principal pathway by which MDMA is metabolized, can also produce clinically relevant interactions with recreational drugs (140). 

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