Pharmacokinetics of oltipraz in mutant Nagase analbuminemic rats.
Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (50 mg/kg) administration to control male Sprague-Dawely rats and mutant Nagase analbuminemic rats (NARs). In NARs, the expression and mRNA level of CYP1A2 increased, and oltipraz was mainly metabolized via CYP1A1/2, 2B1/2, 2C11, 201, and 3A1/2 in male rats. Hence, it may be expected that the CL of oltipraz would be significantly faster in NARs. This was proven by the following results. After intravenous administration, the CL of oltipraz was significantly faster in NARs (125% increase) than controls due to significantly greater free fractions (unbound to plasma proteins) of oltipraz (197% increase) and significantly faster CL(int) for the disappearance of oltipraz (11.4% increase) in NARs, since oltipraz is an intermediate hepatic extraction ratio drug in rats. The V(ss) was significantly larger in NARs (109% increase) and this could be due to significant increase in free fractions of oltipraz in NARs. After oral administration, the AUC of oltipraz was also significantly smaller in NARs (61.9% decrease). This could also be due to significant increase in free fractions of oltipraz and significantly faster CL(int) in NARs. However, this was not due to decrease in absorption in NARs.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Soo K
SK
Bae
Hee E
HE
Kang
Min K
MK
Kang
Jin W
JW
Kim
Taekrho
T
Kim
Myung G
MG
Lee
D000118:Acetylglucosaminidase / Q000235:genetics*; D000284:Administration, Oral; D000418:Albumins / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D019540:Area Under Curve; D001798:Blood Proteins / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D003956:Dialysis; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009154:Mutation / Q000502:physiology; D011485:Protein Binding; D011719:Pyrazines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012556:Schistosomicides / Q000493:pharmacokinetics*; D013871:Thiones; D013876:Thiophenes
D000418:Albumins; D001798:Blood Proteins; D011719:Pyrazines; D012556:Schistosomicides; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D019388:Cytochrome P-450 CYP1A2; D000118:Acetylglucosaminidase