Preclinical absorption, distribution, metabolism, and excretion of an oral amide prodrug of gemcitabine designed to deliver prolonged systemic exposure

Pharmaceutics

Volumn 5, Issue 2, 2013, Pages 261-276

  Wickremsinhe, Enaksha ^a   Bao, Jingqi ^a   Smith, Richard ^a,b   Burton, Richard ^a,b   Dow, Shannon ^a   Perkins, Everett ^a  

^a ELI LILLY AND COMPANY   (United States)

^b IQVIA   (United States)

Author keywords

Carboxylesterase; CES2; Gemcitabine; Prodrug

Indexed keywords

AMIDE; CARBOXYLESTERASE; DEOXYURIDINE DERIVATIVE; DRUG METABOLITE; GEMCITABINE; LSN 198791; LY 2334737; NUCLEOSIDE ANALOG; PRODRUG; PROTEIN CES2; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; DOG; DRUG ABSORPTION; DRUG BILE LEVEL; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG EXCRETION; DRUG EXPOSURE; DRUG FECES LEVEL; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG TISSUE LEVEL; DRUG URINE LEVEL; FEMALE; FIRST PASS EFFECT; HUMAN; HUMAN TISSUE; IN VITRO STUDY; IN VIVO STUDY; INTESTINE EPITHELIUM; MALE; MAXIMUM PLASMA CONCENTRATION; MOUSE; NONHUMAN; RAT; SEX DIFFERENCE; SINGLE DRUG DOSE; STRUCTURE ANALYSIS; SUSTAINED DRUG RELEASE; TIME TO MAXIMUM PLASMA CONCENTRATION;

EID: 84877745217     PISSN: None     EISSN: 19994923     Source Type: Journal    
DOI: 10.3390/pharmaceutics5020261     Document Type: Article

References (36)

1. Burris, H.A.; Moore, M.J.; Andersen, J.; Green, M.R.; Rothenberg, M.L.; Modiano, M.R.; Cripps, M.C.; Portenoy, R.K.; Storniolo, A.M.; Tarassoff, P. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J. Clin. Oncol. 1997, 15, 2403-2413.
2. Hilbig, A.; Oettle, H. Gemcitabine in the treatment of metastatic pancreatic cancer. Expert Rev. Anticanc. 2008, 8, 511-523.
3. Lorusso, D.; di Stefano, A.; Fanfani, F.; Scambia, G. Role of gemcitabine in ovarian cancer treatment. Ann. Oncol. 2006, 17, 188-194.
4. Thigpen, T. The role of gemcitabine in first-line treatment of advanced ovarian carcinoma. Semin. Oncol. 2006, 33, 26-32.
5. Mornex, F.; Girard, N. Gemcitabine and radiation therapy in non-small cell lung cancer: State of the art. Ann. Oncol. 2006, 17, 1743-1747.
6. Favaretto, A.G. Non-platinum combination of gemcitabine in NSCLC. Ann. Oncol. 2006, 17, 82-85.
7. Silvestris, N.; Cinieri, S.; La Torre, I.; Pezzella, G.; Numico, G.; Orlando, L.; Lorusso, V. Role of gemcitabine in metastatic breast cancer patients: A short review. Breast 2008, 17, 220-226.
8. Dent, S.; Messersmith, H.; Trudeau, M. Gemcitabine in the management of metastatic breast cancer: A systematic review. Breast Cancer Res. Treat. 2008, 108, 319-331.
9. Bellmunt, J.; Albiol, S.; de Olano, A.R.; Pujadas, J.; Maroto, P. Gemcitabine in the treatment of advanced transitional cell carcinoma of the urothelium. Ann. Oncol. 2006, 17, 113-117.
10. El Karak, F.; Flechon, A. Gemcitabine in bladder cancer. Expert Opin. Pharmaco. 2007, 8, 3251-3256.
11. Eli Lilly and Company. Gemzar® (gemcitabine HCl) for injection. Package label. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf (accessed on 2 May 2013).
12. Huang, P.; Chubb, S.; Hertel, L.; Grindey, G.; Plunkett, W. Action of 2',2'-difluorodeoxycytidine on DNA synthesis. Cancer Res. 1991, 51, 6110-6117.
13. Ruiz van Haperen, V.; Vererman, G.; Vermorken, J.B.; Peters, G.J. 2',2'-Difluorodeoxycytidine (gemcitabine) incorporation into RNA and DNA from tumour cell lines. Biochem Pharmacol. 1993, 46, 762-766.
14. Plunkett, W.; Huang, P.; Xu, Y.Z.; Heinemann, V.; Grunewald, R.; Gandhi, V. Gemcitabine: Metabolism, mechanisms of action, and self-potentiation. Semin. Oncol. 1995, 22, 3-10.
15. Plunkett, W.; Huang, P.; Searcy, C.E.; Gandhi, V. Gemcitabine: Preclinical pharmacology and mechanism of action. Semin. Oncol. 1996, 23, 3-15.
16. Heinemann, V.; Xu, Y.; Chubb, S.; Sen, A.; Hertel, L.; Grindey, G.; Plunkett, W. Cellular elimination of 2',2'-difluorodeoxycytidine 5'-triphosphate: A mechanism of self-potentiation. Cancer Res. 1992, 52, 533-539.
17. Kroep, J.; van Moorsel, C.; Veerman, G.; Voorn, D.; Schultz, R.; Worzalla, J.; Tanzer, L.; Merriman, R.; Pinedo, H.; Peters, G. Role of deoxycytidine kinase (dCK), thymidine kinase 2 (TK2), and deoxycytidine deaminase (dCDA) in the antitumor activity of gemcitabine (dFdC). Adv. Exp. Med. Biol. 1998, 431, 657-660.
18. Patel, S.R.; Gandhi, V.; Jenkins, J.; Papadopolous, N.; Burgess, M.A.; Plager, C.; Plunkett, W.; Benjamin, R.S. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J. Clin. Oncol. 2001, 19, 3483-3489.
19. Gandhi, V.; Plunkett, W.; Du, M.; Ayres, M.; Estey, E.H. Prolonged Infusion of gemcitabine: Clinical and pharmacodynamic studies during a phase I trial in relapsed acute Myelogenous Leukemia. J. Clin. Oncol. 2002, 20, 665-673.
20. Eckel, F.; Schmelz, R.; Erdmann, J.; Mayr, M.; Lersch, C. Phase II trial of a 24-hour infusion of gemcitabine in previously untreated patients with advanced pancreatic adenocarcinoma. Cancer Invest. 2003, 21, 690-694.
21. Veltkamp, S.A.; Jansen, R.S.; Callies, S.; Pluim, D.; Visseren-Grul, C.M.; Rosing, H.; Kloeker-Rhoades, S.; Andre, V.A.M.; Beijnen, J.H.; Slapak, C.A. et al. Oral Administration of Gemcitabine in Patients with Refractory Tumors: A Clinical and Pharmacologic Study. Clin. Cancer Res. 2008, 14, 3477-3486.
22. Malet-Martino, M.; Martino, R. Clinical studies of 5-fluorouracil (capecitabine, UFT, S-1): A review. Oncologist 2002, 7, 288-323.
23. Ettmayer, P.; Amidon, G.; Clement, B.; Testa, B. Lessons learned from marketed and investigational prodrugs. J. Med. Chem. 2004, 47, 2393-2404.
24. Pazdur, R.; Hoff, P.M.; Medgyesy, D.; Royce, M.; Brito, R.A. The Oral Fluorouracil Prodrugs. Oncology 1998, 12, 48-51.
25. Bender, D.M.; Bao, J.; Dantzig, A.H.; Diseroad, W.D.; Law, K.L.; Magnus, N.A.; Peterson, J.A.; Perkins, E.J.; Pu, Y.J.; Reutzel-Edens, S.M. et al. Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J. Med. Chem. 2009, 52, 6958-6961.
26. Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov. 2008, 7, 255-270.
27. Potter, P.M.; Wadkins, R.M. Carboxylesterases-Detoxifying enzymes and targets for drug therapy. Curr. Med. Chem. 2006, 13, 1045-1054.
28. Yang, C.Y.; Dantzig, A.H.; Pidgeon, C. Intestinal peptide transport systems and oral drug availability. Pharm. Res. 1999, 16, 1331-1343.
29. Davies, B.; Morris, T. Physiological parameters in laboratory animals and humans. Pharm. Res. 1993, 10, 1093-1095.
30. Pratt, S.E.; Durland-Busbice, S.; Shepard, R.L.; Heinz-Taheny, K.; Iversen, P.W.; Dantzig, A.H. Human carboxylesterase 2 hydrolyzes the prodrug of gemcitabine (LY2334737) and confers prodrug sensitivity to cancer cells. Clin. Cancer Res. 2013, 19, 1159-1168.
31. Shipley, L.A.; Brown, T.J.; Cornpropst, D.; Hamilton, M.; Daniels, W.D.; Culp, H.W. Metabolism and disposition of gemcitabine, an oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metab. Dispos. 1992, 20, 849-855.
32. Abbruzzese, J.L.; Grunewald, R.; Weeks, E.A.; Gravel, D.; Adams, T.; Nowak, B.; Mineishi, S.; Tarassoff, P.; Satterlee, W.; Raber, M.N. et al. A Phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J. Clin. Oncol. 1991, 9, 491-498.
33. Satoh, T.; Taylor, P.; Bosron, W.F.; Sanghani, S.P.; Hosokawa, M.; La Du, B.N. Current progress on esterases: From molecular structure to function. Drug Metab. Dispos. 2002, 30, 488-493.
34. Taketani, M.; Shii, M.; Ohura, K.; Ninomiya, S.; Imai, T. Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sci. 2007, 81, 924-932.
35. Sanghani, S.P.; Sanghani, P.C.; Schiel, M.A.; Bosron, W.F. Human Carboxylesterases: An update on CES1, CES2 and CES3. Protein Peptide Lett. 2009, 16, 1207-1214.
36. Pratt, S.E.; Durland-Busbice, S.; Shepard, R.L.; Donoho, G.; Starling, J.J.; Wickremsinhe, E.; Perkins, E.J.; Dantzig, A.H. Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts. Mol. Cancer Ther. 2013, 12, 481-490.