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Plasma Pharmacokinetics, Oral Bioavailability, and Interspecies Scaling of the DNA Methyltransferase Inhibitor, Zebularine

Authors' Affiliations: ¹ Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute and ² Department of Pharmacology and ³ Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; ⁴ Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland; ⁵ Toxicology Research Laboratory, Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and ⁶ Biomedical Simulations Resource, Department of Biomedical Engineering, University of Southern California, Los Angeles, California

Requests for reprints: Merrill J. Egorin, Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Room G27E, Hillman Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-3252; Fax: 412-623-1212; E-mail: egorinmj{at}upmc.edu.

Purpose: Zebularine is a DNA methyltransferase inhibitor proposed for clinical evaluation.

Experimental Design: We developed a liquid chromatography/mass spectrometry assay and did i.v. and oral studies in mice, rats, and rhesus monkeys.

Results: In mice, plasma zebularine concentrations declined with terminal half-lives (t_1/2) of 40 and 91 minutes after 100 mg/kg i.v. and 1,000 mg/kg given orally, respectively. Zebularine plasma concentration versus time curves (area under the curve) after 100 mg/kg i.v. and 1,000 mg/kg given orally were 7,323 and 4,935 µg/mL min, respectively, corresponding to a total body clearance (CL_tb) of 13.65 mL/min/kg, apparent total body clearance (CL_app) of 203 mL/min/kg, and oral bioavailability of 6.7%. In rats, plasma zebularine concentrations declined with t_1/2 of 363, 110, and 126 minutes after 50 mg/kg i.v., 250 mg/kg given orally, and 500 mg/kg given orally, respectively. Zebularine areas under the curve after 50 mg/kg i.v., 250 mg/kg given orally, and 500 mg/kg given orally were 12,526, 1,969, and 7,612 µg/mL min, respectively, corresponding to a CL_tb of 3.99 mL/min/kg for 50 mg/kg i.v. and CL_app of 127 and 66 mL/min/kg for 250 and 500 mg/kg given orally, respectively. Bioavailabilities of 3.1% and 6.1% were calculated for the 250 and 500 mg/kg oral doses, respectively. In monkeys, zebularine t_1/2 was 70 and 150 minutes, CL_tb was 3.55 and 10.85 mL/min/kg after i.v. administration, and CL_app was 886 and 39,572 mL/min/kg after oral administration of 500 and 1,000 mg/kg, respectively. Zebularine oral bioavailability was <1% in monkeys. Interspecies scaling produced the following relationship: CL_tb = 6.46(weight^0.9).

Conclusions: Zebularine has limited oral bioavailability. Interspecies scaling projects a CL_tb of 296 mL/min in humans.

Key Words: DNA methylation • zebularine • pharmacokinetics • bioavailability • interspecies scaling

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