Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate: contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2.
OBJECTIVE
It has been reported that mirodenafil is primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2, 2B1/2, 2D1 and 3A1/2 in rats. It has also been reported that the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 increases and that of hepatic CYP2D1 decreases in rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the pharmacokinetics of mirodenafil were studied in control and U-ARF rats.


METHODS
The pharmacokinetic parameters of mirodenafil and SK3541 (a metabolite of mirodenafil) were compared after the intravenous and oral administration of mirodenafil at a dose of 20 mg/kg to U-ARF and control rats.


RESULTS
After interavenous administration of mirodenafil to U-ARF rats, the total area under the concentration-time curve (AUC) of mirodenafil was significantly smaller (36.5% decrease) than controls, possibly due to the significantly faster non-renal clearance (66.1% increase; because of increase in the protein expression of hepatic CYP3A1) than controls. After the oral administration of mirodenafil to U-ARF rats, the AUC of mirodenafil was also significantly smaller (47.8% decrease) due to the increase in the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 compared with controls.


CONCLUSIONS
After both intravenous and oral administration of mirodenafil to U-ARF rats, the AUC(SK3541)/AUC(mirodenafil) ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.
Choi
Young H
YH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Lee
Young S
YS
Kim
Tae K
TK
Lee
Bong-Y
BY
Lee
Myung G
MG
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014502:Uranyl Nitrate
C528397:N-dehydroxyethylmirodenafil; D011744:Pyrimidinones; D013449:Sulfonamides; D014502:Uranyl Nitrate; C528396:mirodenafil; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A