Pharmacokinetics of theophylline in diabetes mellitus rats: induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation.
Pharmacokinetic parameters of theophylline and one of its metabolites, 1,3-dimethyluric acid (1,3-DMU), were compared after intravenous and oral administration of aminophylline, 5mg/kg as theophylline, to diabetes mellitus rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. In DMIA and DMIS rats, expression of CYP1A2 and 2E1 increased approximately three times. Theophylline was metabolized to 1,3-DMU by CYP1A2 and 2E1 in rats. Hence, it was expected that formation of 1,3-DMU increased in DMIA or DMIS rats. This was proven by the following results. First, after intravenous administration of theophylline, the AUC of 1,3-DMU was significantly greater in DMIA (110% increase) or DMIS (47.4% increase) rats. Second, the AUC of theophylline was significantly smaller in DMIA (26.1% decrease) or DMIS (30.1% decrease) rats because of significantly faster time-averaged total body clearance in DMIA (34.8% increase) or DMIS (42.7% increase) rats. Third, based on in vitro hepatic microsomal studies, intrinsic 1,3-DMU formation clearances were significantly faster in DMIA (20.4% increase) or DMIS (30.7% increase) rats than respective control rats. Similar results (AUC values of theophylline and 1,3-DMU) were also obtained after oral administration.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Kwanak-Gu, Seoul 151-742, South Korea.
Yu Chul
YC
Kim
Ae Kyung
AK
Lee
Joo Hyun
JH
Lee
Inchul
I
Lee
Duk Chul
DC
Lee
So Hee
SH
Kim
Sang Geon
SG
Kim
Myung Gull
MG
Lee
D000284:Administration, Oral; D000496:Alloxan; D000628:Aminophylline / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D004790:Enzyme Induction; D007275:Injections, Intravenous; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013806:Theophylline / Q000097:blood / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
D012333:RNA, Messenger; D014527:Uric Acid; D000628:Aminophylline; D013311:Streptozocin; D000496:Alloxan; D013806:Theophylline; C031274:1,3-dimethyluric acid; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2