This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kreis, W. Articles by Vinciguerra, V. Search for Related Content PubMed PubMed Citation Articles by Kreis, W. Articles by Vinciguerra, V.

Effect of Tetrahydrouridine on the Clinical Pharmacology of 1-ß-D-Arabinofuranosylcytosine When Both Drugs Are Coinfused over Three Hours¹

Division of Hematology/Oncology, Department of Medicine, North Shore University Hospital and Cornell University Medical College [W. K., D. R. B., P. S., S. A., L. W., V. H., J. F., M. D., V. V.], Manhasset, New York; Ciba-Geigy Corporation [K. C.], Ardsley, New York, 10502; and Memorial Sloan-Kettering Cancer Center [M. A.], New York, New York 11021

When 1-ß-D-arabinofuranosylcytosine (ara-C), 25 mg/m², is infused over 3 h together with tetrahydrouridine (THU) at 10 to 350 mg/m² to heavily pretreated patients with solid tumors, Michaelis-Menten type kinetic values are observed with leveling off of area under the curve, ara-C levels at 3 h, and total body clearance after 150 mg/m² of THU. When the ara-C dose was increased to 50, 75, and 100 mg/m² coinfusion of 250 or 350 mg/m² of THU significantly increased plasma ara-C at peak and area under the curve. In contrast, total body clearance and volume of distribution decreased significantly. At 100 mg/m² of ara-C coinfused with high doses of THU, i.e., at 350 mg/m², the pharmacokinetics of plasma ara-C was changed from a biphasic decay of plasma ara-C at peaks (control) to a curve similar or identical to a monophasic curve, indicating that THU not only inhibits deamination but also changes the distribution of ara-C. This combination provides plasma ara-C levels (10 µM) comparable to high dose ara-C at 1 g/m². Such plasma ara-C levels are considered to be sufficient for saturation of the kinases catalyzing the production of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate. This reduced ara-C dose necessary to achieve saturation of kinases also reduces plasma 1-ß-D-arabinofuranosyluracil levels substantially. Toxicity of this combination was predominantly confined to bone marrow and gastrointestinal toxicity.

¹ Supported in part by the Don Monti Memorial Research Foundation, and National Cancer Institute Grant 1 R01 CA38980.

² To whom requests for reprints should be addressed.

Received 7/23/87. Revised 11/30/87. Accepted 12/ 3/87.

This article has been cited by other articles:

				J. H. Beumer, J. L. Eiseman, R. A. Parise, E. Joseph, J. M. Covey, and M. J. Egorin Modulation of Gemcitabine (2',2'-Difluoro-2'-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine Clin. Cancer Res., June 1, 2008; 14(11): 3529 - 3535. [Abstract] [Full Text] [PDF]

				J. H. Beumer, J. L. Eiseman, R. A. Parise, E. Joseph, J. L. Holleran, J. M. Covey, and M. J. Egorin Pharmacokinetics, Metabolism, and Oral Bioavailability of the DNA Methyltransferase Inhibitor 5-Fluoro-2'-Deoxycytidine in Mice Clin. Cancer Res., December 15, 2006; 12(24): 7483 - 7491. [Abstract] [Full Text] [PDF]