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Antimicrobial Agents and Chemotherapy, September 2006, p. 2926-2931, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.01566-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Metabolic Activation of Pradefovir by CYP3A4 and Its Potential as an Inhibitor or Inducer

Chin-chung Lin,* Che Fang, Salete Benetton, Gui-fen Xu, and Li-Tain Yeh

Valeant Research & Development, Costa Mesa, California

Received 8 December 2005/ Returned for modification 14 March 2006/ Accepted 8 June 2006

Metabolic activation of pradefovir to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) was evaluated by using cDNA-expressed CYP isozymes in portal vein-cannulated rats following oral administration and in human liver microsomes. The enzyme induction potential of pradefovir was evaluated in rats following multiple oral dosing and in primary cultures of human hepatocytes. The results indicated that CYP3A4 is the only cDNA-expressed CYP isozyme catalyzing the conversion of pradefovir to PMEA. Pradefovir was converted to PMEA in human liver microsomes with a Km of 60 µM, a maximum rate of metabolism of 228 pmol/min/mg protein, and an intrinsic clearance of about 359 ml/min. Addition of ketoconazole and monoclonal antibody 3A4 significantly inhibits the conversion of pradefovir to PMEA in human liver microsomes, suggesting the predominant role of CYP3A4 in the metabolic activation of pradefovir. Pradefovir at 0.2, 2, and 20 µM was neither a direct inhibitor nor a mechanism-based inhibitor of CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 in human liver microsomes. In rats, the liver was the site of metabolic activation of pradefovir, whereas the small intestine did not play a significant role in the metabolic conversion of pradefovir to PMEA. Daily oral dosing (300 mg/kg of body weight) to rats for 8 days showed that pradefovir was not an inducer of P450 enzymes in rats. Furthermore, pradefovir at 10 µg/ml was not an inducer of either CYP1A2 or CYP3A4/5 in primary cultures of human hepatocytes.

* Corresponding author. Mailing address: Drug Development, Valeant Research & Development, Costa Mesa, CA 92626. Phone: (714) 545-1011. Fax: (714) 641-7201. E-mail: cclin{at}valeant.com.

Antimicrobial Agents and Chemotherapy, September 2006, p. 2926-2931, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.01566-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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