Effects of water deprivation on the pharmacokinetics of DA-8159, a new erectogenic, in rats.
OBJECTIVE
To test the effect of 72 h water deprivation on the non-renal clearance (CL) of DA-8159 in a rat model of dehydration. DA-8159 is mainly metabolized via CYP3A1/2 and the expression and mRNA level of CYP3A1/2 are not affected by dehydration.


METHODS
DA-8159 (30 mg/kg) was administered intravenously or orally to male control Sprague Dawley rats and rat model of dehydration.


RESULTS
As expected, after intravenous administration, the CL(NR) values of DA-8159 were comparable between two groups of rats. This could be supported by comparable intrinsic CL of DA-8159 using hepatic microsomes for both groups of rats. However, the CL was significantly slower in rat model of dehydration due, at least in part, to significantly slower renal CL in rat model of dehydration. The slower CL(R) in rat model of dehydration could be due to urine flow ratedependent renal CL of DA-8159; the less urine output, the less the urinary excretion of unchanged DA-8159. After oral administration, the AUC values of DA-8159 were not significantly different between two groups of rats, although the AUC of DA-8159 in rat model of dehydration was significantly greater than controls after intravenous administration. This could be possibly due to changes in the intestinal first-pass effects in rat model of dehydration.


CONCLUSIONS
After intravenous administration of DA-8159, the non-renal CL values were comparable between two groups of rats due to the lack of effect of dehydration on CYP3A1/2.
Kim
Ji Young
JY
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, South Korea.
Kim
Yu Chul
YC
Lee
Myung Gull
MG
Kwon
Jong Won
JW
Yoo
Moohi
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003681:Dehydration / Q000201:enzymology / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D014868:Water Deprivation; D000096926:Benzenesulfonamides
D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C465138:Cyp3a23-3a1 protein, rat; C419664:udenafil; D000096926:Benzenesulfonamides