TY - JOUR
T1 - Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate
T2 - Contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2
AU - Choi, Young H.
AU - Lee, Young S.
AU - Kim, Tae K.
AU - Lee, Bong Y.
AU - Lee, Myung G.
PY - 2009
Y1 - 2009
N2 - Objectives: 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. Key findings: 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 AUCSK3541/AUCmirodenafil ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.
AB - Objectives: 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. Key findings: 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 AUCSK3541/AUCmirodenafil ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.
UR - http://www.scopus.com/inward/record.url?scp=85047681160&partnerID=8YFLogxK
U2 - 10.1211/jpp.61.10.0008
DO - 10.1211/jpp.61.10.0008
M3 - Article
C2 - 19814864
AN - SCOPUS:85047681160
SN - 0022-3573
VL - 61
SP - 1325
EP - 1332
JO - Journal of Pharmacy and Pharmacology
JF - Journal of Pharmacy and Pharmacology
IS - 10
ER -