Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo.
OBJECTIVE
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.
Ring
Barbara J
BJ
Eli Lilly and Company, Indianapolis, IN 46285, USA.
Patterson
Beverley E
BE
Mitchell
Malcolm I
MI
Vandenbranden
Mark
M
Gillespie
Jennifer
J
Bedding
Alun W
AW
Jewell
Hayley
H
Payne
Christopher D
CD
Forgue
S Thomas
ST
Eckstein
James
J
Wrighton
Steven A
SA
Phillips
Diane L
DL
D000328:Adult; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002243:Carbolines / Q000494:pharmacology*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008148:Lovastatin / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics*; D008875:Middle Aged; D000068581:Tadalafil
D014151:Anti-Anxiety Agents; D000924:Anticholesteremic Agents; D002243:Carbolines; D000068581:Tadalafil; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam