PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of pharmscispringer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
AAPS PharmSci. 2004 March; 6(1): 1–9.
Published online 2004 January 9. doi:  10.1208/ps060101
PMCID: PMC2750936

Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats

Abstract

The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of timedependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg−1 and 0.40 mg kg−1), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg−1), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h−1 kg−1 of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg−1) was ~8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.

References

1. Degos L, Wang ZY. All trans retioic acid in acute promyelocytic leukemia. Oncogene. 2001;20:7140–7145. doi: 10.1038/sj.onc.1204763. [PubMed] [Cross Ref]
2. Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol. 2001;38:13–25. doi: 10.1016/S0037-1963(01)90002-2. [PubMed] [Cross Ref]
3. Reynolds CP, Lemons RS. Retinoid therapy of childhood cancer. Hematol Oncol Clin North Am. 2001;15:867–910. doi: 10.1016/S0889-8588(05)70256-2. [PubMed] [Cross Ref]
4. Camacho LH. Clinical applications of retinoids in cancer medicine. J Biol Regul Homeost Agents. 2003;17:98–114. [PubMed]
5. Conley BA, Egorin MJ, Sridhara R, et al. Van echo DA. Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics. Cancer Chemother Pharmacol. 1997;39:291–299. doi: 10.1007/s002800050575. [PubMed] [Cross Ref]
6. Reynolds CP. Differentiating agents in pediatric malignancies: retinoids in neuroblastoma. Curr Oncol Rep. 2000;2:511–518. doi: 10.1007/s11912-000-0104-y. [PubMed] [Cross Ref]
7. Todesco A, Carli M, Iacoma I, Frascella E, Ninfo V, Rosolen A. All-trans retinoic acid and interferon-alpha in the treatment of a patient with resistant metastatic osteosarcoma. Cancer. 2000;89:2661–2666. doi: 10.1002/1097-0142(20001215)89:12<2661::AID-CNCR20>3.0.CO;2-9. [PubMed] [Cross Ref]
8. Goncalves A, Camerlo J, Bun H, et al. Phase II study of a combination of cisplatin, all-trans-retinoic acid and interferon-alpha in squamous cell carcinoma: clinical results and pharmacokinetics. Anticancer Res. 2001;21:1431–1437. [PubMed]
9. Goldberg JS, Vargas M, Rosmarin AS, et al. Phase I trial of interferon alpha 2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma. Cancer. 2002;95:1220–1227. doi: 10.1002/cncr.10809. [PubMed] [Cross Ref]
10. Adamson PC, Bailey J, Pluda J, et al. Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. J Clin Oncol. 1995;13:1238–1241. [PubMed]
11. Adamson PC, Reaman G, Finklestein JZ, Feusner J, Berg SL, Blaney SM, O brien M, Murphy RF, Balis FM. Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer. J Clin Oncol. 1997;15:3330–3337. [PubMed]
12. Regazzi MB, Iacona I, Gervasutti C, Lazzarino M, Toma S. Clinical pharmacokinetics of tretinoin. Clin Pharmacokinet. 1997;32:382–402. [PubMed]
13. Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. leukemia. 2002;16(10):1940–1958. doi: 10.1038/sj.leu.2402719. [PubMed] [Cross Ref]
14. Torres-Molina F, Peris JE, Garcia-Carbonell MC, Aristorena JC, Granero L, Chesa-Jimenez J. Use of rats chronically cannulated in the jugular vein and the duodenum in pharmacokinetic studies. Effect of ether anesthesia on absorption of amoxicillin. Arzneimittelforschung. 1996;46:716–719. [PubMed]
15. Wagner JG. Pharmacokinetic absorption plots from oral data alone or oral/intravenous data and an exact Loo-Riegelman equation. J Pharm Sci. 1983;72:838–842. doi: 10.1002/jps.2600720738. [PubMed] [Cross Ref]
16. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel Dekker Inc; 1982.
17. Pharsight Corporation Winnonlin. Professional ed 2.1. Pharsight Corporation, 299 California Avenue, Palo Alto, CA; 1998.
18. SPSS for Windows [computer program]. Release 10.0.5, standard version. Chicago, Illinois: SPSS Inc; 1999.
19. Mansouri S, Tod M, Leclerq M, Petitjean O, Perret G, Porthault M. Time-and dose-dependent kinetics of all-trans-retinoic acid in rats after oral or intravenous administration(s) Drug Metab Dispos. 1995;23:227–231. [PubMed]
20. Adamson PC, Balis FM, Smith MA, Murphy RF, Godwin KA, Poplack DG. Dose-dependent pharmacokinetics of all-trans-retinoic acid. J Natl Cancer Inst. 1992;84(17):1332–1335. doi: 10.1093/jnci/84.17.1332. [PubMed] [Cross Ref]
21. Adamson PC. Pharmacokinetics of all-trans retinoic acid: clinical implications in acute promyelocytic leukemia. Semin Hematol. 1994;31:14–17. [PubMed]
22. Wang Y, Zolfaghari R, Ross AC. Cloning of rat cytochrome P450RAI (CYP26) cDNA and regulation of its gene expression by all-trans-retinoic acid in vivo. Arch Biochem Biophys. 2002;401:235–243. doi: 10.1016/S0003-9861(02)00043-7. [PubMed] [Cross Ref]
23. Ozpolat B, Lopez-Berestein G, Admason P, Fu CJ, Williams AH. Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. J Pharm Pharm Sci. [serial online] 2003;6:292–301. [PubMed]
24. Lampen A, Meyer S, Nau H. Effects of receptor-selective retinoids on cyp 26 gene expression and metabolism of all-tras-retinoic acid in intestinal cell. Drug Metab Dispos. 2001;29:742–747. [PubMed]

Articles from AAPS PharmSci are provided here courtesy of American Association of Pharmaceutical Scientists