Avodart (Dutasteride) and Nicotine: Full Interaction Profile

Is there a direct interaction between dutasteride and nicotine?

Avodart is a 0.5 mg soft capsule taken once daily and swallowed whole [1]. It is extensively metabolized by CYP3A4 and CYP3A5, and it is not metabolized by CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 [1]. Peak levels arrive 2 to 3 hours after a dose, absolute bioavailability is about 60%, and the terminal half-life at steady state is about 5 weeks [1].

Nicotine runs through a different enzyme: it is a CYP2A6 substrate [3]. CYP2A6 is not on dutasteride's clearance list [1]. The drugs whose blood levels rise and fall when a person starts or stops smoking are the CYP1A2 substrates. Reviews name caffeine, clozapine, fluvoxamine, olanzapine, tacrine and theophylline as the main ones [2]. Dutasteride is not among them.

Why the smoking enzyme effect stops short of dutasteride

Polycyclic aromatic hydrocarbons in tobacco smoke are potent inducers of CYP1A1 and CYP1A2 (and possibly CYP2E1) [4][2]. Nicotine itself is not the inducer. One review of smoking cessation states that the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, so nicotine replacement will not alter it [5].

This matters for anyone who switches from cigarettes to a patch or gum: the enzyme change follows the smoke, not the nicotine.

Animal data add a small nuance. In one rat study a single nicotine dose raised CYP1A1 activity in lung tissue 4.4-fold at 6 hours and 14.7-fold at 12 hours, returning toward baseline by 24 hours, while liver CYP1A2 protein and mRNA were not significantly changed [6]. The relevance of that to people is unknown.

What the Avodart label does list as interactions

The interaction section of the Avodart label covers these [1]:

• Potent, chronic CYP3A4 inhibitors such as ritonavir. The effect of potent CYP3A4 inhibitors on dutasteride has not been studied, and the label says to use caution [1].
• The calcium channel blockers verapamil and diltiazem. These decrease dutasteride clearance and raise exposure, a change the label does not consider clinically significant, with no dose adjustment recommended [1].
• The alpha blockers tamsulosin and terazosin. Dutasteride does not change their steady-state pharmacokinetics [1].
• Digoxin and warfarin. Dutasteride did not alter digoxin pharmacokinetics or warfarin pharmacokinetics or prothrombin time [1].
• Cholestyramine. A single 5 mg dutasteride dose followed 1 hour later by cholestyramine did not change dutasteride bioavailability [1].

Nicotine and tobacco do not appear in that list [1].

Nicotine's own effects, which are not metabolic

Nicotine is a stimulant that causes peripheral vasoconstriction, faster heart rate and higher blood pressure, and tolerance does not develop to its catecholamine-releasing effects [4]. Smoking blunts the blood-pressure and heart-rate lowering from beta-blockers [4].

A review of nicotine's cardiovascular toxicity concluded that nicotine may contribute to cardiovascular disease through sympathetic stimulation and catecholamine release, but that cigarette smoke contains many other cardiovascular toxins. It also found that cigarettes deliver nicotine faster and usually in higher doses than nicotine replacement, so effects are more intense, and that smoking raises blood coagulability while transdermal nicotine does not appear to. Trials in stable coronary disease suggest nicotine does not raise cardiovascular risk [7]. None of this concerns how dutasteride is absorbed, metabolized or cleared.

Dutasteride's hormone effect

The label lists no smoking or nicotine effect on dutasteride's action [1]. What the label documents is how much dutasteride suppresses the hormone it targets: median serum DHT fell 85% after 1 week and 90% after 2 weeks on 0.5 mg daily, and 94% at 1 year [1].

In the 4-year CombAT trial, 4,844 men were randomized to dutasteride 0.5 mg, tamsulosin 0.4 mg or both. Combination therapy was superior to tamsulosin alone but not to dutasteride alone for reducing acute urinary retention or BPH-related surgery [8].

Quitting smoking changes other medicines, not this one

When heavy smokers stop, CYP1A2 activity falls. In one study of 12 people smoking 20 or more cigarettes a day, caffeine clearance dropped 36.1%, from 2.47 to 1.53 mL/min/kg, with a half-life of decline of 38.6 hours [9]. In an earlier comparison, caffeine half-life was 3.5 hours in 13 smokers versus 6.0 hours in 13 non-smokers, with clearance of 155 versus 94 mL/kg/h [10].

A review of smoking cessation found that dosage adjustments are clearly indicated after quitting for warfarin, olanzapine, clozapine and theophylline, which are CYP1A2 substrates with narrow therapeutic ratios [5]. Dutasteride is not a CYP1A2 substrate [1].

PSA testing while on dutasteride

Dutasteride lowers serum PSA by about 50% within 3 to 6 months [1]. The label says to establish a new PSA baseline at least 3 months after starting, to double an isolated PSA value in a man treated for 3 months or more when comparing with normal values in untreated men, and to evaluate any confirmed rise from the lowest on-treatment value even if it is within the normal range [1]. The percent free PSA ratio stays constant [1]. The label's PSA instructions make no distinction between smokers and non-smokers [1].