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Theophylline pharmacokinetics: comparison of Cyp1a1(−/−) and Cyp1a2(−/−) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-type mice

Derkenne, Sandrine; Curran, Christine P.; Shertzer, Howard G.; Dalton, Timothy P.; Dragin, Nadine; Nebert, Daniel W.

Pharmacogenetics and Genomics: July 2005 - Volume 15 - Issue 7 - p 503-511
doi: 10.1097/01.fpc.0000167326.00411.50
ORIGINAL ARTICLES
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Objectives Pharmacokinetics of theophylline was investigated in Cyp1(+/+) wild-type mice, Cyp1a1(−/−) and Cyp1a2(−/−) knockout mice, and humanized hCYP1A1_1A2 mice lacking either the mouse Cyp1a1 or Cyp1a2 gene.

Methods and results Animals received a single dose of theophylline (8 mg/kg i.p.), either alone or pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 μg/kg i.p.) 24 h prior to theophylline. We found that mouse or human CYP1A2 is the predominant enzyme for theophylline metabolism, the contribution of mouse or human CYP1A1 to theophylline metabolism is negligible, and another TCDD-inducible enzyme plays a minor role in 1-methyluric acid and 1,3-dimethyluric acid formation as well as enhanced theophylline clearance from the body. The half-life of elimination from plasma was more than four times longer in Cyp1a2(−/−) than Cyp1(+/+) mice and more than 10 times different after TCDD pretreatment. In humanized hCYP1A1_1A2 mice lacking the mouse Cyp1a2 gene, the half-life of elimination from plasma was two to three times longer than that in Cyp1(+/+) mice and four to five times different after TCDD pretreatment.

Conclusion Replacement of mouse Cyp1a2 with a functional human CYP1A2 gene restored the ability to metabolize theophylline, and the metabolism changed to a humanized profile (i.e. 3-methylxanthine formation, not seen in the wild-type mouse). TCDD-pretreated hCYP1A1_1A2 Cyp1a2(−/−) mice exhibited enhanced theophylline metabolism and clearance, due to induction of the human CYP1A2 enzyme. Comparing the hCYP1A1_1A2 Cyp1a2(−/−) and wild-type mice with published clinical studies, we found theophylline clearance to be about 5 times and 12 times, respectively, greater than that reported in humans.

Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati OH USA

Correspondence and requests for reprints to Daniel W. Nebert, Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056, USA

Tel: +1 513–558–4239; fax: +1 513–558–0925;

e-mail: dan.nebert@uc.edu

Received 11 February 2005 Accepted 12 April 2005

© 2005 Lippincott Williams & Wilkins, Inc.