Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.
BACKGROUND
Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions.


METHODS
The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration.


RESULTS
Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase.


CONCLUSIONS
Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.
Kivistö
K T
KT
Department of Clinical Pharmacology, University of Helsinki, Finland. kari.kivisto@huch.fi
Villikka
K
K
Nyman
L
L
Anttila
M
M
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000097:blood*; D006207:Half-Life; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000187:drug effects*; D012016:Reference Values; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000097:blood*; D017312:Toremifene / Q000008:administration & dosage / Q000097:blood*
D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D013629:Tamoxifen; D017312:Toremifene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D012293:Rifampin