Tadalafil (Generic) Metabolism and Energy Expenditure: A Clinical Deep Dive

How is tadalafil broken down?

Tadalafil is metabolized mainly by the liver enzyme CYP3A4 [1]. The major circulating metabolite is a catechol metabolite, and the label states that tadalafil's metabolites are not expected to be pharmacologically active [1]. Oral clearance is about 2.5 L per hour [1].

The drug leaves the body as metabolites: about 61% of a dose is excreted in feces and 36% in urine [1]. Less than 0.0005% of a dose appears in semen [1].

Tadalafil is a CYP3A4 substrate. Studies show it does not inhibit or induce CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 [1]. The label also reports no significant effect of tadalafil on warfarin exposure or prothrombin time, on midazolam or lovastatin exposure, on digoxin at steady state, or on aspirin-related bleeding time, and only a small 3 beats-per-minute addition to theophylline's heart-rate effect [1].

How fast does it get in, and how long does it last?

Peak levels occur between 30 minutes and 6 hours after a dose, with a median of 2 hours, and food does not change the rate or extent of absorption [1]. The volume of distribution is about 63 L and 94% of the drug is protein bound [1]. Mean terminal half-life is 17.5 hours [1].

With once-daily dosing, steady state is reached within 5 days, with exposure about 1.6-fold that of a single dose, so the label says daily use gives continuous blood levels [1]. The Cialis label reports improved erectile function compared with placebo for up to 36 hours after a dose; this does not mean a continuous erection, and sexual stimulation is still required [1].

What raises or lowers tadalafil levels?

Drugs that inhibit or induce CYP3A4 change tadalafil exposure substantially.

Ketoconazole 400 mg daily raised tadalafil 20 mg exposure (AUC) by 312% and peak concentration by 22%; ketoconazole 200 mg daily raised tadalafil 10 mg AUC by 107% [1]. Ritonavir 200 mg twice daily raised tadalafil 20 mg AUC by 124% with no change in peak level, while ritonavir 500 or 600 mg twice daily raised AUC by 32% and lowered peak level by 30% [1]. Erythromycin, itraconazole and grapefruit juice were not studied with tadalafil, but the label says they would likely increase exposure [1].

With potent CYP3A4 inhibitors, the Cialis label caps as-needed use at 10 mg no more often than every 72 hours and once-daily use at 2.5 mg [1]. The Adcirca label says to avoid tadalafil for pulmonary arterial hypertension in people taking potent CYP3A inhibitors such as ketoconazole and itraconazole [2].

Rifampin 600 mg daily cut tadalafil 10 mg AUC by 88% and peak concentration by 46% [1]. The Cialis label calls for no dose adjustment, but notes that once-daily efficacy may fall by an unknown amount; carbamazepine, phenytoin and phenobarbital would likely lower exposure but were not studied [1]. The Adcirca label says to avoid the drug in people chronically taking potent inducers such as rifampin [2].

Kidney and liver changes

For Cialis, the label reports dose limits in renal impairment, including a 5-mg starting dose and a maximum of 10 mg no more often than every 48 hours at a creatinine clearance of 30 to 50 mL/min; below 30 mL/min or on hemodialysis the maximum is 5 mg no more often than every 72 hours, and once-daily use is not recommended [1]. Exposure is about doubled in mild (51 to 80 mL/min) or moderate (31 to 50 mL/min) renal impairment after single 5 to 10 mg doses, according to the Adcirca label [2].

For mild or moderate liver impairment (Child-Pugh A or B), the Cialis label limits the as-needed dose to 10 mg; for severe impairment (Child-Pugh C) it says Cialis is not recommended [1]. The Adcirca label says to consider starting at 20 mg once daily in mild to moderate cirrhosis and to avoid the drug in severe cirrhosis [2].

Exposure is 25% higher in healthy men aged 65 or older [1].

Does tadalafil raise energy expenditure or metabolic rate?

Tadalafil is not labeled for this. The approved uses are erectile dysfunction, BPH, the two together, and pulmonary arterial hypertension; weight loss and diabetes are not listed indications [1][2].

The drug does act on a pathway found in many tissues. Tadalafil blocks phosphodiesterase type 5 (PDE5), the enzyme that breaks down cyclic GMP, and the label lists PDE5 in pulmonary vascular smooth muscle, visceral smooth muscle, corpus cavernosum, skeletal muscle, platelets, kidney, lung, cerebellum and pancreas [1][2]. In vitro, tadalafil is about 700-fold more potent for PDE5 than for PDE6 in the retina, and 14-fold (PDE11A1) and 40-fold (PDE11A4) more potent for PDE5 than for PDE11; the label says the clinical consequence of PDE11 inhibition in humans has not been defined [1].

What the label says about combining it with other drugs

Nitrates in any form, regularly or intermittently, are contraindicated with Cialis because the label says tadalafil potentiates their blood-pressure-lowering effect [1]. In a life-threatening situation, the label says at least 48 hours should elapse after the last Cialis dose before a nitrate is considered, and then only under close medical supervision with hemodynamic monitoring [1]. In a 150-man study, more men taking tadalafil had standing systolic pressure below 85 mm Hg after nitroglycerin at 4, 8 and 24 hours; greater mean maximal falls were measured at 8 and 24 hours [3].

Tadalafil and alpha-blockers both lower blood pressure, and the effect is additive [1]. For erectile dysfunction, the label says to be stable on the alpha-blocker first and to start tadalafil at the lowest dose; for BPH the combination is not recommended [1]. Substantial alcohol, 5 units or more, with Cialis can increase orthostatic symptoms such as a faster heart rate, lower standing blood pressure, dizziness and headache; tadalafil did not change alcohol levels and alcohol did not change tadalafil levels [1].