Transport of a new erectogenic udenafil in Caco-2 cells.
P-glycoprotein, an ATP-dependent efflux pump, is a membrane transporter that influences the absorption and excretion of drugs. There is a striking overlap between the substrates for CYP3A4 and P-glycoprotein. This study was designed to assess whether udenafil, a substrate of CYP3A4, is also a P-glycoprotein substrate. Udenafil stimulated P-glycoprotein ATPase activity, a putative measure of P-glycoprotein affinity, although with lower affinity than a proven substrate, verapamil. Bidirectional transport studies of udenafil using Caco-2 cell monolayers showed that its efflux (15.9-22.8 x 10(-6) cm/s) was significantly higher than its influx (3.7-9.1 x 10(-6) cm/s). P-glycoprotein inhibitors such as cyclosporine, tariquidar and verapamil significantly increased the influx of udenafil and decreased the efflux of udenafil. These results indicate that udenafil is a substrate for P-glycoprotein. The low bioavailability, variable absorption and drug-drug interactions of udenafil may be related to the variability of CYP3A4 and P-glycoprotein expression and to possible CYP3A4 and P-glycoprotein interactions.
Ji
Hye Young
HY
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, Wonkwang University, Iksan 570-749, Korea.
Shim
Hyun Joo
HJ
Yoo
Moohi
M
Park
Eun-Seok
ES
Lee
Hye Suk
HS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C510163:CYP3A4 protein, human; C419664:udenafil; D000096926:Benzenesulfonamides