Interaction between udenafil and tamsulosin in rats: non-competitive inhibition of tamsulosin metabolism by udenafil via hepatic CYP3A1/2.
OBJECTIVE
Orthostatic hypotension has been observed when PDE 5 (cGMP-specific phosphodiesterase type 5) inhibitors are co-administered with alpha-adrenoceptor antagonists. Here we assessed the pharmacokinetic and haemodynamic interactions between udenafil and tamsulosin in rats, as both drugs are metabolized via rat hepatic cytochrome P450 3A1/2.


METHODS
Interactions between the two drugs were evaluated in rats after simultaneous 1 or 15 min i.v. infusion or after p.o. administration of udenafil (30 mg x kg(-1)) and/or tamsulosin (1 mg x kg(-1)). In vitro metabolism of tamsulosin with udenafil was measured to obtain the inhibition constant (K(i)) and [I]/K(i) ratio of udenafil.


RESULTS
The total area under the plasma concentration-time curve from time zero to time infinity (AUC)s (or AUC(0-4 h)) of tamsulosin were significantly greater after 15 min of i.v. infusion or after oral administration with udenafil, compared with tamsulosin alone. The hepatic first-pass metabolism of tamsulosin was inhibited by udenafil, and the inhibition in vitro was in a non-competitive mode. The arterial systolic blood pressure was significantly lower at 5, 10 and 60 min after oral co-administration of the drugs.


CONCLUSIONS
The significantly greater AUC of tamsulosin after i.v. and p.o. administration of both drugs may be attributable to non-competitive inhibition of cytochrome P450 3A1/2-mediated hepatic tamsulosin metabolism by udenafil. The inhibition was also observed in human liver S9 fractions, suggesting that a reassessment of the oral dosage of tamsulosin is necessary when udenafil and tamsulosin are co-administered to patients with benign prostatic hyperplasia.
Kang
H E
HE
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Bae
S K
SK
Yoo
M
M
Lee
D C
DC
Kim
Y G
YG
Lee
M G
MG
D000284:Administration, Oral; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D004336:Drug Antagonism; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077409:Tamsulosin; D000096926:Benzenesulfonamides
D000317:Adrenergic alpha-Antagonists; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D008565:Membrane Proteins; D058986:Phosphodiesterase 5 Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000077409:Tamsulosin; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides