Skip to main content
Erschienen in: Cancer Chemotherapy and Pharmacology 2/2011

01.02.2011 | Original Article

Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice

verfasst von: Jan H. Beumer, Julie L. Eiseman, Judith A. Gilbert, Julianne L. Holleran, Archibong E. Yellow-Duke, Dana M. Clausen, David Z. D’Argenio, Matthew M. Ames, Pamela A. Hershberger, Robert A. Parise, Lihua Bai, Joseph M. Covey, Merrill J. Egorin

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Cytidine drugs, such as gemcitabine, undergo rapid catabolism and inactivation by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine analogue metabolism. However, THU is only 20% orally bioavailable, which limits its preclinical evaluation and clinical use. Therefore, we characterized THU pharmacokinetics after the administration to mice of the more lipophilic pro-drug triacetyl-THU (taTHU).

Methods

Mice were dosed with 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC–MS/MS assay. Plasma and urine pharmacokinetic parameters were calculated non-compartmentally and compartmentally.

Results

taTHU did not inhibit CD. THU, after 150 mg/kg taTHU i.v., had a 235-min terminal half-life and produced plasma THU concentrations >1 μg/mL, the concentration shown to inhibit CD, for 10 h. Renal excretion accounted for 40–55% of the i.v. taTHU dose, 6–12% of the p.o. taTHU dose. A two-compartment model of taTHU generating THU fitted the i.v. taTHU data best. taTHU, at 150 mg/kg p.o., produced a concentration versus time profile with a plateau of approximately 10 μg/mL from 0.5–2 h, followed by a decline with a 122-min half-life. Approximately 68% of i.v. taTHU is converted to THU. Approximately 30% of p.o. taTHU reaches the systemic circulation as THU.

Conclusions

The availability of THU after p.o. taTHU is 30%, when compared to the 20% achieved with p.o. THU. These data will support the clinical studies of taTHU.
Literatur
1.
Zurück zum Zitat Akaike H (1979) A Bayesian extension of the minimal AIC procedures of autoregressive model fitting. Biometrika 66:237–242CrossRef Akaike H (1979) A Bayesian extension of the minimal AIC procedures of autoregressive model fitting. Biometrika 66:237–242CrossRef
2.
Zurück zum Zitat Ashour OM, Naguib FN, el Kouni MH (1996) 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′, 3′, 5′-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. Biochem Pharmacol 51:1601–1611CrossRefPubMed Ashour OM, Naguib FN, el Kouni MH (1996) 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′, 3′, 5′-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. Biochem Pharmacol 51:1601–1611CrossRefPubMed
3.
Zurück zum Zitat Beumer JH, Eiseman JL, Parise RA, Florian JA Jr, Joseph E, D’Argenio DZ, Parker RS, Kay B, Covey JM, Egorin MJ (2008) Plasma pharmacokinetics and oral bioavailability of 3, 4, 5, 6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice. Cancer Chemother Pharmacol 62:457–464CrossRefPubMed Beumer JH, Eiseman JL, Parise RA, Florian JA Jr, Joseph E, D’Argenio DZ, Parker RS, Kay B, Covey JM, Egorin MJ (2008) Plasma pharmacokinetics and oral bioavailability of 3, 4, 5, 6-tetrahydrouridine, a cytidine deaminase inhibitor, in mice. Cancer Chemother Pharmacol 62:457–464CrossRefPubMed
4.
Zurück zum Zitat Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ (2008) Modulation of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 3, 4, 5, 6-tetrahydrouridine. Clin Cancer Res 14:3529–3535CrossRefPubMed Beumer JH, Eiseman JL, Parise RA, Joseph E, Covey JM, Egorin MJ (2008) Modulation of gemcitabine (2′, 2′-difluoro-2′-deoxycytidine) pharmacokinetics, metabolism, and bioavailability in mice by 3, 4, 5, 6-tetrahydrouridine. Clin Cancer Res 14:3529–3535CrossRefPubMed
5.
Zurück zum Zitat Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, Egorin MJ (2006) Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine in mice. Clin Cancer Res 12:7483–7491CrossRefPubMed Beumer JH, Eiseman JL, Parise RA, Joseph E, Holleran JL, Covey JM, Egorin MJ (2006) Pharmacokinetics, metabolism, and oral bioavailability of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine in mice. Clin Cancer Res 12:7483–7491CrossRefPubMed
6.
Zurück zum Zitat Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, Egorin MJ (2008) Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol 62:363–368CrossRefPubMed Beumer JH, Parise RA, Newman EM, Doroshow JH, Synold TW, Lenz HJ, Egorin MJ (2008) Concentrations of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine (FdCyd) and its cytotoxic metabolites in plasma of patients treated with FdCyd and tetrahydrouridine (THU). Cancer Chemother Pharmacol 62:363–368CrossRefPubMed
7.
Zurück zum Zitat Creasey WA, Fink ME, Handschumacher RE, Calabresi P (1963) Clinical and pharmacological studies with 2′, 3′, 5′-triacetyl-6-azauridine. Cancer Res 23:444–453PubMed Creasey WA, Fink ME, Handschumacher RE, Calabresi P (1963) Clinical and pharmacological studies with 2′, 3′, 5′-triacetyl-6-azauridine. Cancer Res 23:444–453PubMed
8.
Zurück zum Zitat D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los Angeles
9.
Zurück zum Zitat Dareer SM, Mulligan LT Jr, White V, Tillery K, Mellett LB, Hill DL (1977) Distribution of [3H]cytosine arabinoside and its products in mice, dogs, and monkeys and effect of tetrahydrouridine. Cancer Treat Rep 61:395–407PubMed Dareer SM, Mulligan LT Jr, White V, Tillery K, Mellett LB, Hill DL (1977) Distribution of [3H]cytosine arabinoside and its products in mice, dogs, and monkeys and effect of tetrahydrouridine. Cancer Treat Rep 61:395–407PubMed
10.
Zurück zum Zitat Doolittle CH, McDonald CJ, Calabresi P (1977) Pharmacological studies of neurotoxicity in patients with psoriasis treated with azaribine, utilizing high-pressure liquid chromatography. J Lab Clin Med 90:773–785PubMed Doolittle CH, McDonald CJ, Calabresi P (1977) Pharmacological studies of neurotoxicity in patients with psoriasis treated with azaribine, utilizing high-pressure liquid chromatography. J Lab Clin Med 90:773–785PubMed
11.
Zurück zum Zitat Doroshow JH, McCoy S, Macdonald JS, Issell BF, Patel T, Cobb PW, Yost KJ, Abbruzzese JL (2006) Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a southwest oncology group study. Invest New Drugs 24:537–542CrossRefPubMed Doroshow JH, McCoy S, Macdonald JS, Issell BF, Patel T, Cobb PW, Yost KJ, Abbruzzese JL (2006) Phase II trial of PN401, 5-FU, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach: a southwest oncology group study. Invest New Drugs 24:537–542CrossRefPubMed
13.
Zurück zum Zitat el Dareer SM, White V, Chen FP, Mellett LB, Hill DL (1976) Distribution of tetrahydrouridine in experimental animals. Cancer Treat Rep 60:1627–1631PubMed el Dareer SM, White V, Chen FP, Mellett LB, Hill DL (1976) Distribution of tetrahydrouridine in experimental animals. Cancer Treat Rep 60:1627–1631PubMed
14.
Zurück zum Zitat Ellison G, Straumfjord JV Jr, Hummel JP (1958) Buffer capacities of human blood and plasma. Clin Chem 4:452–461PubMed Ellison G, Straumfjord JV Jr, Hummel JP (1958) Buffer capacities of human blood and plasma. Clin Chem 4:452–461PubMed
15.
Zurück zum Zitat Fenaux P (2005) Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol 2(Suppl 1):S36–S44CrossRefPubMed Fenaux P (2005) Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol 2(Suppl 1):S36–S44CrossRefPubMed
16.
Zurück zum Zitat Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794–1803CrossRefPubMed Gilbert JA, Salavaggione OE, Ji Y, Pelleymounter LL, Eckloff BW, Wieben ED, Ames MM, Weinshilboum RM (2006) Gemcitabine pharmacogenomics: cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794–1803CrossRefPubMed
17.
Zurück zum Zitat Greer S, Schwade J, Marion HS (1995) Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation. Int J Radiat Oncol Biol Phys 32:1059–1069CrossRefPubMed Greer S, Schwade J, Marion HS (1995) Five-chlorodeoxycytidine and biomodulators of its metabolism result in fifty to eighty percent cures of advanced EMT-6 tumors when used with fractionated radiation. Int J Radiat Oncol Biol Phys 32:1059–1069CrossRefPubMed
18.
Zurück zum Zitat Hale JT, Bigelow JC, Mathews LA, McCormack JJ (2002) Analytical and pharmacokinetic studies with 5-chloro-2′-deoxycytidine. Biochem Pharmacol 64:1493–1502CrossRefPubMed Hale JT, Bigelow JC, Mathews LA, McCormack JJ (2002) Analytical and pharmacokinetic studies with 5-chloro-2′-deoxycytidine. Biochem Pharmacol 64:1493–1502CrossRefPubMed
19.
Zurück zum Zitat Handschumacher RE, Creasey WA, Fink ME, Calabresi P, Welch AD (1962) Pharmacological and clinical studies with triacetyl 6-azauridine. Cancer Chemother Rep 16:267–269PubMed Handschumacher RE, Creasey WA, Fink ME, Calabresi P, Welch AD (1962) Pharmacological and clinical studies with triacetyl 6-azauridine. Cancer Chemother Rep 16:267–269PubMed
20.
Zurück zum Zitat Hidalgo M, Villalona-Calero MA, Eckhardt SG, Drengler RL, Rodriguez G, Hammond LA, Diab SG, Weiss G, Garner AM, Campbell E, Davidson K, Louie A, O’Neil JD, von Borstel R, Von Hoff DD, Rowinsky EK (2000) Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies. J Clin Oncol 18:167–177PubMed Hidalgo M, Villalona-Calero MA, Eckhardt SG, Drengler RL, Rodriguez G, Hammond LA, Diab SG, Weiss G, Garner AM, Campbell E, Davidson K, Louie A, O’Neil JD, von Borstel R, Von Hoff DD, Rowinsky EK (2000) Phase I and pharmacologic study of PN401 and fluorouracil in patients with advanced solid malignancies. J Clin Oncol 18:167–177PubMed
21.
Zurück zum Zitat Ho DH, Bodey GP, Hall SW, Benjamin RS, Brown NS, Freireich EJ, Loo TL (1978) Clinical pharmacology of tetrahydrouridine. J Clin Pharmacol 18:259–265PubMed Ho DH, Bodey GP, Hall SW, Benjamin RS, Brown NS, Freireich EJ, Loo TL (1978) Clinical pharmacology of tetrahydrouridine. J Clin Pharmacol 18:259–265PubMed
22.
Zurück zum Zitat Kaye SB (1998) New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer 78(Suppl 3):1–7CrossRefPubMed Kaye SB (1998) New antimetabolites in cancer chemotherapy and their clinical impact. Br J Cancer 78(Suppl 3):1–7CrossRefPubMed
23.
Zurück zum Zitat Klubes P, Geffen DB, Cysyk RL (1986) Comparison of the bioavailability of uridine in mice after either oral or parenteral administration. Cancer Chemother Pharmacol 17:236–240CrossRefPubMed Klubes P, Geffen DB, Cysyk RL (1986) Comparison of the bioavailability of uridine in mice after either oral or parenteral administration. Cancer Chemother Pharmacol 17:236–240CrossRefPubMed
24.
Zurück zum Zitat Kreis W, Chan K, Budman DR, Schulman P, Allen S, Weiselberg L, Lichtman S, Henderson V, Freeman J, Deere M (1988) Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours. Cancer Res 48:1337–1342PubMed Kreis W, Chan K, Budman DR, Schulman P, Allen S, Weiselberg L, Lichtman S, Henderson V, Freeman J, Deere M (1988) Effect of tetrahydrouridine on the clinical pharmacology of 1-beta-D-arabinofuranosylcytosine when both drugs are coinfused over three hours. Cancer Res 48:1337–1342PubMed
25.
Zurück zum Zitat Kreis W, Woodcock TM, Gordon CS, Krakoff IH (1977) Tetrahydrouridine: physiologic disposition and effect upon deamination of cytosine arabinoside in man. Cancer Treat Rep 61:1347–1353PubMed Kreis W, Woodcock TM, Gordon CS, Krakoff IH (1977) Tetrahydrouridine: physiologic disposition and effect upon deamination of cytosine arabinoside in man. Cancer Treat Rep 61:1347–1353PubMed
26.
Zurück zum Zitat Lyko F, Brown R (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 97:1498–1506CrossRefPubMed Lyko F, Brown R (2005) DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst 97:1498–1506CrossRefPubMed
27.
Zurück zum Zitat Marsh JH, Kreis W, Barile B, Akerman S, Schulman P, Allen SL, DeMarco LC, Schuster MW, Budman DR (1993) Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin. Cancer Chemother Pharmacol 31:481–484CrossRefPubMed Marsh JH, Kreis W, Barile B, Akerman S, Schulman P, Allen SL, DeMarco LC, Schuster MW, Budman DR (1993) Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin. Cancer Chemother Pharmacol 31:481–484CrossRefPubMed
28.
Zurück zum Zitat Mekras JA, Boothman DA, Greer SB (1985) Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies. Cancer Res 45:5270–5280PubMed Mekras JA, Boothman DA, Greer SB (1985) Use of 5-trifluoromethyldeoxycytidine and tetrahydrouridine to circumvent catabolism and exploit high levels of cytidine deaminase in tumors to achieve DNA- and target-directed therapies. Cancer Res 45:5270–5280PubMed
29.
Zurück zum Zitat Neil GL, Moxley TE, Kuentzel SL, Manak RC, Hanka LJ (1975) Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. Cancer Chemother Rep 59:459–465PubMed Neil GL, Moxley TE, Kuentzel SL, Manak RC, Hanka LJ (1975) Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. Cancer Chemother Rep 59:459–465PubMed
30.
Zurück zum Zitat Neil GL, Moxley TE, Manak RC (1970) Enhancement by tetrahydrouridine of 1-beta-D-arabinofuranosylcytosine (cytarabine) oral activity in L1210 leukemic mice. Cancer Res 30:2166–2172PubMed Neil GL, Moxley TE, Manak RC (1970) Enhancement by tetrahydrouridine of 1-beta-D-arabinofuranosylcytosine (cytarabine) oral activity in L1210 leukemic mice. Cancer Res 30:2166–2172PubMed
31.
Zurück zum Zitat Newman EM, Longmate J, Lenz H, Carroll M, Stalter S, Lim D, Raschko D, Shibata S, Somlo G, Doroshow J (2002) Phase I and clinical pharmacokinetic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine: a California Cancer Consortium study. Proceedings of the American Society of Clinical Oncology 21:108a Newman EM, Longmate J, Lenz H, Carroll M, Stalter S, Lim D, Raschko D, Shibata S, Somlo G, Doroshow J (2002) Phase I and clinical pharmacokinetic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine: a California Cancer Consortium study. Proceedings of the American Society of Clinical Oncology 21:108a
32.
Zurück zum Zitat Parise RA, Egorin MJ, Eiseman JL, Joseph E, Covey JM, Beumer JH (2007) Quantitative determination of the cytidine deaminase inhibitor tetrahydrouridine (THU) in mouse plasma by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 21:1991–1997CrossRefPubMed Parise RA, Egorin MJ, Eiseman JL, Joseph E, Covey JM, Beumer JH (2007) Quantitative determination of the cytidine deaminase inhibitor tetrahydrouridine (THU) in mouse plasma by liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 21:1991–1997CrossRefPubMed
33.
Zurück zum Zitat Saif MW, von Borstel R (2006) 5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice. Cancer Chemother Pharmacol 58:136–142CrossRefPubMed Saif MW, von Borstel R (2006) 5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice. Cancer Chemother Pharmacol 58:136–142CrossRefPubMed
35.
Zurück zum Zitat van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HM (1991) Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst 83:437–441CrossRefPubMed van Groeningen CJ, Peters GJ, Nadal JC, Laurensse E, Pinedo HM (1991) Clinical and pharmacologic study of orally administered uridine. J Natl Cancer Inst 83:437–441CrossRefPubMed
36.
Zurück zum Zitat von Borstel R, O’Neil J, Bamat M (2009) Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. Proc Am Soc Clin Oncol 27:15s von Borstel R, O’Neil J, Bamat M (2009) Vistonuridine: an orally administered, life-saving antidote for 5-fluorouracil (5FU) overdose. Proc Am Soc Clin Oncol 27:15s
37.
Zurück zum Zitat Wong PP, Currie VE, Mackey RW, Krakoff IH, Tan CT, Burchenal JH, Young CW (1979) Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside. Cancer Treat Rep 63:1245–1249PubMed Wong PP, Currie VE, Mackey RW, Krakoff IH, Tan CT, Burchenal JH, Young CW (1979) Phase I evaluation of tetrahydrouridine combined with cytosine arabinoside. Cancer Treat Rep 63:1245–1249PubMed
Metadaten
Titel
Plasma pharmacokinetics and oral bioavailability of the 3,4,5,6-tetrahydrouridine (THU) prodrug, triacetyl-THU (taTHU), in mice
verfasst von
Jan H. Beumer
Julie L. Eiseman
Judith A. Gilbert
Julianne L. Holleran
Archibong E. Yellow-Duke
Dana M. Clausen
David Z. D’Argenio
Matthew M. Ames
Pamela A. Hershberger
Robert A. Parise
Lihua Bai
Joseph M. Covey
Merrill J. Egorin
Publikationsdatum
01.02.2011
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-010-1337-6

Weitere Artikel der Ausgabe 2/2011

Cancer Chemotherapy and Pharmacology 2/2011 Zur Ausgabe

Announcement

Announcement

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.