Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of rat
Abstract
We have measured the pharmacokinetics of three retinoids, all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in rat blood and rat brain [especially white matter (WM) and gray matter (GM)] to help select retinoids for treating human malignant glioma. All-trans retinoic acid permeated well into the WM, giving peak concentration in WM of 25.7 microg/g, 6 to 7 times higher than the peak serum concentration. There was less 13-cis retinoic acid in WM: area under the curve (AUC)(0-->infinity) WM/AUC(0-->infinity) serum = 18.00 microg ml(-1) h/32.67 microg ml(-1) h. The ratio WM/GM was over 1 for these two compounds, but the half-lives were short in the serum and cerebral tissue (0.57-1.02 h). Fenretinide had different pharmacokinetics: the peak concentrations were in serum (1.7 microg/ml) and WM (1.2 microg/ml)-low, but the AUC(0-->infinity) was large (25.55 microg ml(-1) in serum and 57.53 microg ml(-1) in WM) due to its long elimination half-life (13.78 h in serum and 17.77 h in WM). These findings provide information that may be used to select a retinoid and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.
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ATRA is a small molecule that readily enters tissues and is concentrated in the brain compartments when administered systemically.
“ATRA is a small molecule that readily enters tissues and is concentrated in the brain compartments when administrated systemically (Kurlandsky et al., 1995;Le Doze et al., 2000).”
From Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model (2008) · cites this paper as Le Doze et al., 2000
Cites
Estimates of the worldwide incidence of 25 major cancers in 1990
Parkin, D. M., Pisani, P., & Ferlay, J. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990315)80:6 · Cited by 2,013 · see citing works
Survival and Functional Status after Resection of Recurrent Glioblastoma Multiforme
Barker, F. G., Chang, S. M., Gutin, P. H., Malec, M. K., McDermott, M. W., Prados, M. D., & Wilson, C. B. (1998) · Neurosurgery · doi:10.1097/00006123-199804000-00013 · Cited by 330 · see citing works
Characterization of the role of IL‐6 in the progression of prostate cancer
Chung, T., Yu, J.-Q., Spiotto, M., Bartkowski, M., & Simons, J. (1999) · The Prostate · doi:10.1002/(sici)1097-0045(19990215)38:3 · Cited by 253 · see citing works
Orfanos, C. E., Ehlert, R., & Gollnick, H. P. M. (1987) · Drugs · doi:10.2165/00003495-198734040-00003 · Cited by 250 · see citing works
Formelli, F., Clerici, M., Campa, T., Mauro, M. G. D., Magni, A., Mascotti, G., Moglia, D., Palo, G. D., Costa, A., & Veronesi, U. (1993) · Journal of Clinical Oncology · doi:10.1200/jco.1993.11.10.2036 · Cited by 196 · see citing works
Chang, S. M., Kuhn, J. G., Rizzo, J. D., Robins, H. I., Schold, S. C., Spence, A. M., Berger, M. S., Mehta, M. P., Bozik, M. E., Pollack, I. F., et al. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.6.2188 · Cited by 166 · see citing works
Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid.
Yung, W. K. A., Kyritsis, A. P., Gleason, M. J., & Levin, V. A. (1996) · PubMed · Cited by 122 · see citing works
Zheng, Y. (1999) · Carcinogenesis · doi:10.1093/carcin/20.2.255 · Cited by 116 · see citing works
Food Increases the Bioavailability of Isotretinoin
Colburn, W. A., Gibson, D. M., WIENS, R. E., & Hanigan, J. J. (1983) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1983.tb01800.x · Cited by 101 · see citing works
Mologni, L., Ponzanelli, I., Bresciani, F., Sardiello, G., Bergamaschi, D., Gianni’, M., Reichert, U., Rambaldi, A., Terao, M., & Garattini, E. (1999) · Blood · doi:10.1182/blood.v93.3.1045 · Cited by 88 · see citing works
Defer, G., Adle‐Biassette, H., Ricolfi, F., Martin, L., Authier, F., Chomienne, C., Degos, L., & Degos, J. (1997) · Journal of Neuro-Oncology · doi:10.1023/a:1005701507111 · Cited by 64 · see citing works
Self-citationDirks, P. B., Patel, K., Hubbard, S. L., Ackerley, C. A., Hamel, P. A., & Rutka, J. T. (1997) · Oncogene · doi:10.1038/sj.onc.1201392 · Cited by 62 · see citing works
Chang, S. M., Kuhn, J. G., Robins, H. I., Schold, S. C., Spence, A. M., Berger, M. S., Mehta, M. P., Bozik, M. E., Pollack, I., Schiff, D., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.3.984 · Cited by 61 · see citing works
The treatment of recurrent cerebral gliomas with all-trans-retinoic acid (tretinoin)
Kaba, S. E., Kyritsis, A. P., Conrad, C. A., Gleason, M. J., Newman, R. A., Levin, V. A., & Yung, W. K. A. (1997) · Journal of Neuro-Oncology · doi:10.1023/a:1005743707803 · Cited by 56 · see citing works
Clinical Pharmacokinetics of Tretinoin
Regazzi, M. B., Iacona, I., Gervasutti, C., Lazzarino, M., & Toma, S. (1997) · Clinical Pharmacokinetics · doi:10.2165/00003088-199732050-00004 · Cited by 56 · see citing works
Disposition of all-trans-retinoic acid in mice following oral doses.
Kalin, J. R., Starling, M., & Hill, D. L. (1981) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)06128-8 · Cited by 54 · see citing works
Wyss, R. (1990) · Journal of Chromatography B Biomedical Sciences and Applications · doi:10.1016/s0378-4347(00)82292-6 · Cited by 54 · see citing works
N-(4-hydroxyphenyl)-all-trans-retinamide pharmacokinetics in female rats and mice.
Hultin, T. A., May, C. M., & Moon, R. C. (1986) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)09000-2 · Cited by 53 · see citing works
Wang, C. C., Campbell, S., Furner, R. L., & Hill, D. L. (1980) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)00221-1 · Cited by 52 · see citing works
Kligman, A. M. (1998) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(98)70437-2 · Cited by 48 · see citing works
Pharmacokinetics of N-(4-hydroxyphenyl)-all-trans-retinamide in rats.
Swanson, B. N., Zaharevitz, D. W., & Sporn, M. B. (1980) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)00248-x · Cited by 42 · see citing works
Blood Level Studies of All-trans- and 13-cis-Retinoic Acids in Rats Using Different Formulations
Shelley, R., Jun, H. W., Price, J. C., & Cadwallader, D. E. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710816 · Cited by 32 · see citing works
Irving, H., Lovat, P. E., Hewson, Q. C., Malcolm, A. J., Pearson, A. D. J., & Redfern, C. P. F. (1998) · European Journal of Cancer · doi:10.1016/s0959-8049(97)10027-2 · Cited by 29 · see citing works
Current research and future developments in retinoids: oral and topical agents.
Chandraratna, R. A. S. (1998) · PubMed · Cited by 20 · see citing works
Absorption of tretinoin in rats and rabbits following oral and dermal application.
Chou, R. C., Bürgin, H., Schmitt, G., & Eggers, H. (1997) · PubMed · Cited by 8 · see citing works
Pharmacokinetics of Parenteral 13-cis-Retinoic Acid Formulations in Rats
Guchelaar, H., Wouda, S. H., Beukeveld, G. J. J., Mulder, N. H., & Oosterhuis, J. W. (1992) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600810508 · Cited by 4 · see citing works
The rapid assessment of fatigue severity in cancer patients
Mendoza, T. R., Wang, X. S., Cleeland, C. S., Morrissey, M., Johnson, B. A., Wendt, J. K., & Huber, S. L. (1999) · Cancer · doi:10.1002/(sici)1097-0142(19990301)85:5 · Cited by 1 · see citing works
Single-dose pharmacokinetic study of 13-cis-retinoic acid in man.
Besner, J., Leclaire, R., Band, P. R., Meloche, S., Deschamps, M., Mailhot, S., Moisan, R., & Diorio, G. (1985) · PubMed · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 29 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Retinoic acid in the development, regeneration and maintenance of the nervous system
Maden, M. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2212 · Cited by 896 · see citing works
Ding, Y., Qiao, A., Wang, Z., Goodwin, J. S., Lee, E.-S., Block, M. L., Allsbrook, M., McDonald, M. P., & Fan, G.-H. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.3153-08.2008 · Cited by 269 · see citing works
An analysis of reports of depression and suicide in patients treated with isotretinoin
Wysowski, D. K., Pitts, M., & Beitz, J. G. (2001) · Journal of the American Academy of Dermatology · doi:10.1067/mjd.2001.117730 · Cited by 226 · see citing works
Jaeckle, K. A., Hess, K. R., Yung, W. K. A., Greenberg, H. S., Fine, H. A., Schiff, D., Pollack, I. F., Kuhn, J. G., Fink, K., Mehta, M. P., et al. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.12.097 · Cited by 149 · see citing works
Binan, L., Tendey, C., Crescenzo, G. D., El‐Ayoubi, R., Ajji, A., & Jolicœur, M. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.09.097 · Cited by 138 · see citing works
Jiang, X., Cao, H. Q., Shi, L. Y., Ng, S., Stanton, L. W., & Chew, S. Y. (2011) · Acta Biomaterialia · doi:10.1016/j.actbio.2011.11.019 · Cited by 125 · see citing works
All-transretinoic acid as a novel therapeutic strategy for Alzheimer’s disease
Lee, H. P., Casadesús, G., Zhu, X., Lee, H., Perry, G. L., Smith, M. A., Gustaw‐Rothenberg, K., & Lerner, A. J. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.86 · Cited by 120 · see citing works
Wagner, E. F. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.12.1244 · Cited by 120 · see citing works
Carotenoids and Alzheimer’s Disease: An insight into therapeutic role of retinoids in animal models
Obulesu, M., Dowlathabad, M. R., & Bramhachari, P. V. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.04.004 · Cited by 115 · see citing works
Puduvalli, V. K., Yung, W. K. A., Hess, K. R., Kuhn, J. G., Groves, M. D., Levin, V. A., Zwiebel, J. A., Chang, S. M., Cloughesy, T. F., Junck, L., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.09.096 · Cited by 88 · see citing works
Retinoic acid is detected at relatively high levels in the CNS of adult rats
Werner, E. A., & DeLuca, H. F. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00280.2001 · Cited by 85 · see citing works
Ceramide Signaling in Fenretinide-induced Endothelial Cell Apoptosis
Erdreich‐Epstein, A., Tran, L. B., Bowman, N. N., Wang, H., Cabot, M. C., Durden, D. L., Vlckova, J., Reynolds, C. P., Stins, M. F., Groshen, S. G., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m209962200 · Cited by 84 · see citing works
Calzà, L., Giuliani, A., Fernández, M., Pirondi, S., D’Intino, G., Aloe, L., & Giardino, L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1132092100 · Cited by 80 · see citing works
Štěrba, J., Valík, D., Múdry, P., Kepák, T., Pavelka, Z., Bajčiová, V., Zitterbart, K., Kadlecová, V., & Mazánek, P. (2006) · Oncology Research and Treatment · doi:10.1159/000093474 · Cited by 72 · see citing works
Jeong, Y., Kang, M.-K., Sun, H.-S., Kang, S.-S., Kim, H., Moon, K., Lee, K.-J., Kim, S.-H., & Jung, S. (2004) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2003.12.012 · Cited by 67 · see citing works
Banerjee, S. S., & Chen, D. (2008) · Nanotechnology · doi:10.1088/0957-4484/19/26/265602 · Cited by 63 · see citing works
NRF2 as a determinant of cellular resistance in retinoic acid cytotoxicity
Tan, K. P., Kosuge, K., Yang, M., & Ito, S. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.09.010 · Cited by 62 · see citing works
Maurer, B. J., Kalous, O., Yesair, D. W., Wu, X., Janeba, J., Maldonado, V., Khankaldyyan, V., Frgala, T., Sun, B.-C., McKee, R. T., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1889 · Cited by 61 · see citing works
Li, C., Xue-bo, Y., Chen, X., Meng, Q., & Zhou, J. (2010) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2010.06.019 · Cited by 57 · see citing works
Romer, K. A., de Rooij, D. G., Kojima, M. L., & Page, D. C. (2018) · Developmental Biology · doi:10.1016/j.ydbio.2018.08.009 · Cited by 43 · see citing works
Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch
Lin, W., Jia, X., Shi, X., He, Q., Zhang, P., Zhang, X., Zhang, L., Wu, M., Ren, T., Liu, Y., et al. (2025) · Science · doi:10.1126/science.adp0176 · Cited by 39 · see citing works
Hummel, R., Ulbrich, S., Appel, D., Li, S., Hirnet, T., Zander, S., Bobkiewicz, W., Gölz, C., & Schäfer, M. K. E. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15259 · Cited by 38 · see citing works
Preliminary evidence that abscisic acid improves spatial memory in rats
Qi, C., Ge, J., & Zhou, J. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.11.053 · Cited by 39 · see citing works
Retinoic acid signaling in axonal regeneration
Puttagunta, R., & Giovanni, S. D. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2011.00059 · Cited by 37 · see citing works
Chen, S., Samuel, W., Fariss, R. N., Duncan, T. E., Kutty, R. K., & Wiggert, B. O. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01608.x · Cited by 37 · see citing works
Vitamin A deficiency alters rat lung alveolar basement membrane Reversibility by retinoic acid
Esteban-Pretel, G., Marín, M. P., Renau‐Piqueras, J., Barber, T., & Timoneda, J. (2009) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2008.12.007 · Cited by 36 · see citing works
Chatterjee, A., & Chatterji, U. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2011.09.011 · Cited by 29 · see citing works
RA–RAR-β counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression
Puttagunta, R., Schmandke, A., Floriddia, E. M., Gaub, P., Fomin-Thunemann, N., Ghyselinck, N. B., & Giovanni, S. D. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201102066 · Cited by 28 · see citing works
Ferguson, S. A., Cisneros, F. J., Gough, B., & Ali, S. F. (2005) · Food and Chemical Toxicology · doi:10.1016/j.fct.2005.02.016 · Cited by 28 · see citing works
Ferguson, S. A., Siitonen, P. H., Cisneros, F. J., Gough, B., & Young, J. F. (2006) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2006.pto_359.x · Cited by 25 · see citing works
Natural and synthetic retinoids afford therapeutic effects on intracerebral hemorrhage in mice
Matsushita, H., Hijioka, M., Hisatsune, A., Isohama, Y., Shudo, K., & Katsuki, H. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.03.023 · Cited by 23 · see citing works
Bu, P., & Wan, Y. Y. (2007) · BMC Cancer · doi:10.1186/1471-2407-7-236 · Cited by 23 · see citing works
Kumar, M., Sharma, G., Singla, D., Singh, S., Sahwney, S., Chauhan, A. S., Singh, G., & Kaur, I. P. (2013) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2013.12.011 · Cited by 19 · see citing works
Medina, D. X., Chung, E. P., Bowser, R. P., & Sirianni, R. W. (2019) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2019.04.013 · Cited by 19 · see citing works
Crockett, S., Clarke, M., Reeves, S., & Sims, B. (2011) · Neuroreport · doi:10.1097/wnr.0b013e3283494359 · Cited by 17 · see citing works
Chen, S., Fariss, R. N., Kutty, R. K., Nelson, R., & Wiggert, B. O. (2006) · PubMed · Cited by 15 · see citing works
Grauer, O. M., Pascher, C., Hartmann, C. J., Zeman, F., Weller, M., Proescholdt, M. A., Brawanski, A. T., Pietsch, T., Wick, W., Bogdahn, U., et al. (2011) · Journal of Neuro-Oncology · doi:10.1007/s11060-011-0548-y · Cited by 11 · see citing works
Murine toxicology and pharmacokinetics of novel retinoic acid metabolism blocking agents
Patel, J. B., Khandelwal, A., Chopra, P., Handratta, V. D., & Njar, V. C. O. (2007) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-007-0438-3 · Cited by 10 · see citing works
Synergy of retinoic acid and BH3 mimetics in MYC(N)-driven embryonal nervous system tumours
Seiboldt, T., Zeiser, C., Nguyen, D., Çelikyürekli, S., Herter, S., Najafi, S., Stroh-Dege, A., Meulenbroeks, C., Mack, N. L., Salem-Altintas, R., et al. (2024) · British Journal of Cancer · doi:10.1038/s41416-024-02740-5 · Cited by 9 · see citing works
Lee, J. I., Nguyen, V. T., Chen, M., & Adamson, P. C. (2007) · Journal of Chromatography B · doi:10.1016/j.jchromb.2007.10.044 · Cited by 9 · see citing works
How Do Retinoids Affect Alzheimer’s Disease and Can They Be Novel Drug Candidates?
Alsharief, M. (2024) · Cureus · doi:10.7759/cureus.57548 · Cited by 8 · see citing works
Dong, W., & Zhang, Y. (2018) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2018.6639 · Cited by 6 · see citing works
Cho, H. E., & Kang, M. H. (2016) · Journal of Pharmaceutical and Biomedical Analysis · doi:10.1016/j.jpba.2016.09.046 · Cited by 6 · see citing works
Vitamine A et vieillissement cérébral
Pallet, V., & Enderlin, V. (2011) · Oléagineux Corps gras Lipides · doi:10.1051/ocl.2011.0375 · Cited by 3 · see citing works
Godbole, A. M., Purushottamachar, P., Martin, M. S., & Njar, V. C. O. (2012) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-012-1877-z · Cited by 2 · see citing works
Chang, A., Mae, B., Pei, P., Shea, F., Wang, D., Raymond, J. E., Mallery, S. R., & Lahann, J. (2025) · Macromolecular Bioscience · doi:10.1002/mabi.202400661 · Cited by 2 · see citing works
The Imperceptible Contagion: Arsenic as a Neuro-Immune-Endocrine Disruptor
Chatterjee, A., Jamal, Z., Das, J., Banerjee, A. T., & Chatterji, U. (2021) · Proceedings of the Zoological Society · doi:10.1007/s12595-021-00393-3 · Cited by 2 · see citing works
Inhibitors of EGFR Signaling Retard Cytotoxicity of Fenretinide in Rat Gliosarcoma Cells
Zaheer, A., Sahu, S. K., & Traynelis, V. C. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9401-2 · Cited by 1 · see citing works
Daubric, M. H. (2001) · Cited by 1 · see citing works
Bu, P. (2009) · KU ScholarWorks (The University of Kansas)
Dawson, M. I. (2010) · Wiley eBooks · doi:10.1002/0471266949.bmc065.pub2
- Authors
- Doze, F. L., Debruyne, D., Albessard, F., Barre, L., & Defer, G. L.
- ORCID
- Defer, Gilles Louis
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2000-02
- Volume
- 28
- Issue
- 2
- Pages
- 205-208
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W1495133903
- Cited by
- 54
- References
- 29
- Citations by year
- 2025: 2 · 2024: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- all-trans retinoic acid, isotretinoin, fenretinide, retinoids, pharmacokinetics, brain penetration, white matter, gray matter, high-grade glioma, tissue distribution, elimination half-life
- MeSH terms
- Animals, Antineoplastic Agents, Brain, Chromatography, High Pressure Liquid, Half-Life, Injections, Intraperitoneal, Male, Tretinoin, Rats, Sprague-Dawley, Fenretinide, Area Under Curve, Rats
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