Pharmacokinetics of theophylline in diabetes mellitus rats: induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation.

Abstract

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.

• Authors: Yu Chul Kim, Ae Kyung Lee, Joo Hyun Lee, Inchul Lee, Duk Chul Lee, So Hee Kim, Sang Geon Kim, Myung Gull Lee
• Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences (Eur J Pharm Sci) Vol. 26 Issue 1 Pg. 114-23 (Sep 2005) ISSN: 0928-0987 [Print] Netherlands
• PMID: 15985363 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Uric Acid
• Aminophylline
• Streptozocin
• Alloxan
• Theophylline
• 1,3-dimethyluric acid
• Cytochrome P-450 CYP2E1
• Cytochrome P-450 CYP1A2

Topics

• Administration, Oral
• Alloxan
• Aminophylline (administration & dosage, pharmacokinetics)
• Animals
• Cytochrome P-450 CYP1A2 (biosynthesis, genetics)
• Cytochrome P-450 CYP2E1 (biosynthesis, genetics)
• Diabetes Mellitus, Experimental (chemically induced, metabolism)
• Enzyme Induction
• Injections, Intravenous
• Male
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Streptozocin
• Theophylline (blood, pharmacokinetics)
• Uric Acid (analogs & derivatives, blood, pharmacokinetics)