Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo.

OBJECTIVES: Tadalafil was examined in vitro and in vivo for its ability to affect human cytochrome P450 (CYP) 3A-mediated metabolism. METHODS: Reversible and mechanism-based inhibition of CYP3A by tadalafil was examined in human liver microsomes. The ability of tadalafil to influence CYP3A activity was also examined in primary cultures of human hepatocytes. The effect of tadalafil on the pharmacokinetics of CYP3A probe substrates was evaluated in human volunteers before and after coadministration with either a single dose or multiple doses of tadalafil (10 or 20 mg). RESULTS: Negligible competitive inhibition of CYP3A was observed in vitro. Mechanism-based inhibition of CYP3A was detected, albeit with a low potency. In human hepatocytes, exposure to 1 micromol/L or greater of tadalafil resulted in increased CYP3A protein expression; however, as with a combined effect of induction and inhibition, a corresponding increase in CYP3A activity did not occur. The clinical pharmacokinetics of midazolam and lovastatin, probe substrates of CYP3A, were unaffected by up to 14 days of tadalafil administration (90% confidence intervals for the ratio of least squares means for the pharmacokinetic parameters of tadalafil were contained within the no-effect boundaries of 0.7 to 1.43). CONCLUSIONS: In vitro results suggested that tadalafil would have little effect on the pharmacokinetics of drugs metabolized by CYP3A. Clinical studies demonstrated that the pharmacokinetics of 2 different CYP3A substrates, midazolam and lovastatin, were virtually unchanged after tadalafil coadministration. Thus therapeutic concentrations of tadalafil do not produce clinically significant changes in the clearance of drugs metabolized by CYP3A.

Atomoxetine hydrochloride: clinical drug-drug interaction prediction and outcome.

In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.