Abstract
Orally administered drugs may gain access to the systemic circulation via absorption into the portal blood or by transport through the intestinal lymphatic system. In the majority of cases, absorption via the portal blood is the predominant pathway as portal blood flow, relative to intestinal lymph flow, is orders of magnitude higher (approximately 500-fold). However, for some highly lipophilic compounds, their association and interaction with enterocyte-derived lymph lipoproteins may be sufficient to overcome the differences in relative blood/lymph flow rates resulting in the lymphatics becoming a quantitatively important drug transport pathway.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bagchus WM, Houwing NS, Schnabel P, Lass H, and Thomsen T. Conference Proceedings of the 4th World Congress on the Aging Male, Prague, Czech Republic, February 2004. The Aging Male. 2004; 7:24
Beadle JR, Kini GD, Aldern KA, Gardner MF, Wright KN, Richman DD, and Hostetler KY. Alkylthioglycerol Prodrugs of Foscarnet: Synthesis, Oral Bioavailability and Structure-activity Studies in Human Cytomegalovirus-, Herpes Simplex virus Type 1-and Human Immunodeficiency Virus Type 1-infected Cells. Antivir Chem Chemother 1998; 9:33–40
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, and Perucca E. Progress Report on New Antiepileptic Drugs: A Summary of the Fourth Eilat Conference (EILAT IV). Epilepsy Res 1999; 34:1–41
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, and Perucca E. Progress Report on New Antiepileptic Drugs: A Summary of the Fifth Eilat Conference (EILAT V). Epilepsy Res 2001; 43:11–58
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, and Perucca E. Progress Report on New Antiepileptic Drugs: A Summary of the Sixth Eilat Conference (EILAT VI). Epilepsy Res 2002; 51:31–71
Bibby DC, Charman WN, Charman S A, Iskandar MN, and Porter CJH. Synthesis and Evaluation of 5′ Alkyl Ester Prodrugs of Zidovudine for Directed Lymphatic Delivery. Int J Pharm 1996; 144:61–70
Busbee DL, Yoo JSH, Norman JO, and Joe CO. Polychlorinated Biphenyl Uptake and Transport by Lymph and Plasma Components. Proc Soc Exp Biol Med 1985; 179:116–122
Carter GW, Young PR, Swett LR, and Paris GY. Pharmacological Studies in the Rat with [2-(1,3-didecanoyloxy)-propyl]2-acetyloxybenzoate (A-45474): An Aspirin Pro-Drug with Negligible Gastric Irritation. Agents Actions 1980; 10:240–245
Charman WN. Lipid Vehicle and Formulation Effects on Intestinal Lymphatic Drug Transport. In: Charman W N and Stella VJ. Lymphatic Transport of Drugs Boca Raton: CRC Press; 1992:113–179
Charman WN, Noguchi T, and Stella VJ. An Experimental System Designed to Study the in situ Intestinal Lymphatic Transport of Drugs in Anaesthetized Rats. Int J Pharmaceut 1986; 33:155–164
Charman WN and Porter CJH. Lipophilic Prodrugs Designed for Intestinal Lymphatic Transport. Adv Drug Deliv Rev 1996; 19:149–169
Charman WN and Stella V J. Effect of Lipid Class and Lipid Vehicle Volume on the Intestinal Lymphatic Transport of DDT. Int J Pharmaceut 1986a; 33:165–172
Charman WN and Stella VJ. Estimating the Maximal Potential for Intestinal Lymphatic Transport of Lipophilic Drug Molecules. Int J Pharmaceut 1986b; 34:175–178
Ciesla SL, Trahan J, Wan WB, Beadle JR, Aldern KA, Painter GR, and Hostetler KY. Esterification of Cidofovir with Alkoxyalkanols Increases Oral Bioavailability and Diminishes Drug Accumulation in Kidney. Antiviral Res 2003; 59:163–171
Coert A, Geelen J, de Visser J, and van der Vies J. The Pharmacology and Metabolism of Testosterone Undecanoate (TU), A New Orally Active Androgen. Acta Endocrinol (Copenh) 1975; 79:789–800
Daggett PR, Wheeler MJ, and Nabarro JD. Oral Testosterone, A Reappraisal. Horm Res 1978; 9:121–129
Deverre JR, Loiseau P, Couvreur P, Letourneux Y, Gayral P, and Benoit JP. In-vitro Evaluation of Filaricidal Activity of GABA and 1,3-Dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: A Diglyceride Prodrug. J Pharm Pharmacol 1989; 41:191–193
Deverre JR, Loiseau P, Gayral P, Letourneux Y, Couvreur P, and Benoit JP. In vitro and in vivo Evaluation of Macrofilaricidal Activity of GABA and 1,3-Dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: A Diglyceride Prodrug. Pharm Acta Helv 1992a; 67:349–352
Deverre JR, Loiseau P, Puisieux F, Gayral P, Letourneux Y, Couvreur P, and Benoit JP. Synthesis of the Orally Macrofilaricidal and Stable Glycerolipidic Prodrug of Melphalan, 1,3-Dipalmitoyl-2-(4′(bis(2″-chloroethyl)amino)phenylalaninoyl) glycerol. Arzneimittelforschung 1992b; 42:1153–1156
Edwards GA, Porter CJ, Caliph SM, Khoo SM, and Charman WN. Animal Models for the Study of Intestinal Lymphatic Drug Transport. Adv Drug Deliv Rev 2001; 50:45–60
Elkihel L, Loiseau PM, Bourass J, Gayral P, and Letourneux Y. Synthesis and Orally Macrofilaricidal Evaluation of Niclosamide Lymphotropic Prodrugs. Arzneimittelforschung 1994; 44:1259–1264
Fernandez E and Borgstrom B. Intestinal Absorption of Retinol and Retinyl Palmitate. Effects of Tetrahydrolipstatin. Lipids 1990; 25:549–552
Fisher RS and Ho J. Potential New Methods for Antiepileptic Drug Delivery. CNS Drugs 2002; 16:579–593
Garzon-Aburbeh A, Poupaert JH, Claesen M, Dumont P, and Atassi G. 1. 3-Dipalmitoylglycerol Ester of Chlorambucil as a Lymphotropic, Orally Administrable Antineoplastic Agent. J Med Chem 1983; 26:1200–1203
Garzon-Aburbeh A, Poupaert JH, Claesen M, and Dumont P. A Lymphotropic Prodrug of L-Dopa: Synthesis, Pharmacological Properties, and Pharmacokinetic Behavior of 1,3-Dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl] propane-1,2,3-triol. J Med Chem 1986; 29:687–691
Grimus RC and Schuster I. The Role of the Lymphatic Transport in the Enteral Absorption of Naftifine by the Rat. Xenobiotica 1984; 14:287–294
Hesse GW, Jacob JN, and Shashoua VE. Uptake in Brain and Neurophysiological Activity of Two Lipid Esters of gamma-Aminobutyric Acid. Neuropharmacology 1988; 27:637–640
Hirschhauser C, Hopkinson CR, Sturm G, and Coert A. Testosterone Undecanoate: A New Orally Active androgen. Acta Endocrinol (Copenh) 1975; 80:179–187
Horst HJ, Holtje WJ, Dennis M, Coert A, Geelen J, and Voigt KD. Lymphatic Absorption and Metabolism of Orally Administered Testosterone Undecanoate in Man. Klin Wochenschr 1976; 54:875–879
Hostetler KY, Beadle JR, Kini GD, Gardner MF, Wright KN, Wu TH, and Korba BA. Enhanced Oral Absorption and Antiviral Activity of 1-O-octadecyl-snglycero-3-phospho-acyclovir and Related Compounds in Hepatitis B Virus Infection, in vitro. Biochem Pharmacol 1997; 53:1815–1822
Humberstone AJ and Charman WN. Lipid Based Vehicles for the Oral Delivery of Poorly Water Soluble Drugs. Adv Drug Deliv Rev 1997; 25:103–128
Ichihashi T, Kinoshita H, Takagishi Y, and Yamada H. Intrinsic Lymphatic Partition Rate of Mepitiostane, Epitiostanol, and Oleic Acid Absorbed from Rat Intestine. Pharm Res 1991a; 8:1302–1306
Ichihashi T, Kinoshita H, and Yamada H. Absorption and Disposition of Epithiosteroids in Rats (2): Avoidance of First-Pass Metabolism of Mepitiostane by Lymphatic Absorption. Xenobiotica 1991b; 21:873–880
Ichihashi T, Kinoshita H, Takagishi Y, and Yamada H. Effect of Bile on Absorption of Mepitiostane by the Lymphatic System in Rats. J Pharm Pharmacol 1992a; 44:565–569
Ichihashi T, Kinoshita H, Takagishi Y and Yamada H. Effect of Oily Vehicles on Absorption of Mepitiostane by the Lymphatic System in Rats. J Pharm Pharmacol 1992b; 44:560–564
Isoherranen N, Yagen B, and Bialer M. Isoherranen N, Yagen B, and Bialer M. New CNS-active Drugs Which Are Second-generation Valproic Acid: Can They Lead to the Development of a Magic Bullet? Curr Opin Neurol 2003; 16:203–211
Jacob JN, Hesse GW, and Shashoua VE. gamma-Aminobutyric Acid Esters. 3. Synthesis, Brain Uptake, and Pharmacological Properties of C-18 Glyceryl Lipid Esters of GABA with Varying Degree of Unsaturation. J Med Chem 1987; 30:1573–1576
Jacob JN, Hesse GW, and Shashoua VE. Synthesis, Brain Uptake, and Pharmacological Properties of a Glyceryl Lipid Containing GABA and the GABA-T Inhibitor gamma-Inyl-GABA. J Med Chem 1990; 33:733–736
Jacob JN, Shashoua VE, Campbell A, and Baldessarini RJ. gamma-Aminobutyric Acid Esters. 2. Synthesis, Brain Uptake, and Pharmacological Properties of Lipid Esters of gamma-Aminobutyric Acid. J Med Chem 1985; 28:106–110
Khoo SM, Edwards GA, Porter CJ, and Charman WN. A Conscious Dog Model for Assessing the Absorption, Enterocyte-based Metabolism, and Intestinal Lymphatic Transport of Halofantrine. J Pharm Sci 2001; 90:1599–1607
Khoo SM, Prankerd RJ, Edwards GA, Porter CJ, and Charman WN. A Physicochemical Basis for the Extensive Intestinal Lymphatic Transport of a Poorly Lipid Soluble Antimalarial, Halofantrine Hydrochloride, after Postprandial Administration to Dogs. J Pharm Sci 2002; 91:647–659
Khoo SM, Shackleford DM, Porter CJH, Edwards GA, and Charman WN. Intestinal Lymphatic Transport of Halofantrine Occurs after Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs. Pharm Res 2003; 20:1460–1465
Kini GD, Hostetler SE, Beadle JR, and Aldern KA. Synthesis and Antiviral Activity of 1-O-Octadecyl-2-O-alkyl-sn-glycero-3-foscarnet Conjugates in Human Cytomegalovirus-infected Cells. Antiviral Res 1997; 36:115–124
Kucera GL, Goff CL, Iyer N, Morris-Natschke S, Ishaq KS, Wyrick SD, Fleming RA, and Kucera LS. Cellular Metabolism in Lymphocytes of a Novel Thioether-Phospholipid-AZT Conjugate with Anti-HIV-1 Activity. Antiviral Res 2001; 50:129–137
Kuksis A. Absorption of Fat Soluble Vitamins. In: Kuksis A. Fat Absorption Boca Raton: CRC Press; 1987:65–86
Kumar R and Billimoria JD. Gastric Ulceration and the Concentration of Salicylate in Plasma in Rats after Administration of 14C-Labelled Aspirin and Its Synthetic Triglyceride, 1,3-Dipalmitoyl-2(2′-acetoxy-[14C]carboxylbenzoyl) glycerol. J Pharm Pharmacol 1978; 30:754–758
Kurz M and Scriba GK. Drug-phospholipid Conjugates As Potential Prodrugs: Synthesis, Characterization, and Degradation by Pancreatic Phospholipase A(2). Chem Phys Lipids 2000; 107:143–157
Labiner D M. DP-VPA D-Pharm. Curr Opin Invest Drugs 2002; 3:921–923
Laher JM, Rigler MW, Vetter RD, Barrowman JA, and Patton JS. Similar Bioavailability and Lymphatic Transport of Benzo(A)pyrene when Administered to Rats in Different Amounts of Dietary Fat. J Lipid Res 1984; 25:1337–1342
Lambert DM. Rationale and Applications of Lipids as Prodrug Carriers. Eur J Pharm Sci 2000; 11:S15–S27
Lambert DM, Mergen F, Berens CF, Poupaert JH, and Dumont P. Synthesis and Pharmacological Properties of 2-[S-acetylthiorphan]-1,3-diacylaminopropan-2-ol Derivatives as Chimeric Lipid Drug Carriers Containing an Enkephalinase Inhibitor. Pharm Res 1995; 12:187–191
Loiseau PM, Bourass J, and Letourneux Y. Lymphotropic Antifilarial Agents Derived from Closantel and Chlorambucil. Int J Parasitol 1997; 27:443–447
Loiseau PM, Deverre JR, el Kihel L, Gayral P, and Letourneux Y. Study of Lymphotropic Targeting and Macrofilaricidal Activity of a Melphalan Prodrug on the Molinema dessetae Model. J Chemother 1994; 6:230–237
Maisey NM, Bingham J, Marks V, English J, and Chakraborty J. Clinical Efficacy of Testosterone Undecanoate in Male Hypogonadism. Clin Endocrinol (Oxf) 1981; 14:625–629
Mantelli S, Speiser P, and Hauser H. Phase Behaviour of a Diglyceride Prodrug: Spontaneous Formation of Unilamellar Vesicles. Chem Phys Lipids 1985; 37:329–343
McIntosh MP, Batey AJ, Porter CJ, Charman WN, and Coker S. Desbutylhalofantrine: Evaluation of QT Prolongation and Other Cardiovascular Effects after Intravenous Administration in vivo. J Cardiovasc Pharmacol 2003; 41:406–413
Mergen F, Lambert DM, Goncalves Saraiva JC, Poupaert JH, and Dumont P. Antiepileptic Activity of 1,3-Dihexadecanoylamino-2-valproyl-propan-2-ol, a Prodrug of Valproic Acid Endowed with a Tropism for the Central Nervous System. J Pharm Pharmacol 1991; 43:815–816
Mishima M, Kobayashi S, Abe S, and Yamato C. Metabolic Fate of Indometacin Farnesil a Prodrug of Indomethacin: Characteristic Biotransformation of Indomethacin Farnesil in Rats. Xenobiotica 1990; 20:135–146
Morris-Natschke SL, Ishaq KS and Kucera LS. Morris-Natschke SL, Ishaq KS and Kucera LS. Phospholipid Analogs against HIV-1 Infection and Disease. 1 Infection and Disease. Curr Pharm Des 2003; 9:1441–1451
Nakamura T, Aoyama Y, Fujita T, and Katsui G. Studies on Tocopherol Derivatives: V. Intestinal Absorption of Several d,1-3,4-3H2-(-tocopheryl Esters in the Rat. Lipids 1975; 10:627–633
Noguchi T, Charman WN, and Stella VJ. The Effect of Drug Lipophilicity and Lipid Vehicles on the Lymphatic Absorption of Various Testosterone Esters. Int J Pharmaceut 1985; 24:173–184
Nordskog BK, Phan CT, Nutting DF, and Tso P. An Examination of the Factors Affecting Intestinal Lymphatic Transport of Dietary Lipids. Adv Drug Deliv Rev 2001; 50:21–44
O’Driscoll CM. Lipid-based Formulations for Intestinal Lymphatic Delivery. Eur J Pharm Sci 2002; 15:405–415
Palin KJ and Wilson CJ. The Effect of Different Oils on the Absorption of Probucol in the Rat. J Pharm Pharmacol 1984; 36:641–643
Paris GY and Cimon DG. Glycerides as Prodrugs. 4. Synthesis and Antiinflammatory Activity of 1,3-Dialkanoyl-2-arylalkanoylglycerides. Eur J Med Chem 1982; 17:193–195
Paris GY, Garmaise DL, Cimon DG, Swett L, Carter GW, and Young P. Glycerides as Prodrugs. 1. Synthesis and Antiinflammatory Activity of 1,3-bis(Alkanoyl)-2-(O-acetylsalicyloyl)glycerides (Aspirin Triglycerides). J Med Chem 1979; 22:683–687
Paris GY, Garmaise DL, Cimon DG, Swett L, Carter GW, and Young P. Glycerides as Prodrugs. 2. 1,3-Dialkanoyl-2-(2-methyl-4-oxo-1,3-benzodioxan-2-yl)glycerides (Cyclic Aspirin Triglycerides) As Antiinflammatory Agents. J Med Chem 1980a; 23:79–82
Paris GY, Garmaise DL, Cimon DG, Swett L, Carter GW, and Young P. Glycerides as Prodrugs. 3. Synthesis and Antiinflammatory Activity of [1-(p-Chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyl]glycerides (Indomethacin Glycerides). J Med Chem 1980b; 23:9–13
Poirier H, Degrace P, Niot I, Bernard A, and Besnard P. Localization and Regulation of the Putative Membrane Fatty-Acid Transporter (FAT) in the Small Intestine. Comparison With Fatty Acid-Binding Proteins (FABP). Eur J Biochem 1996; 238:368–373
Porter CJ and Charman WN. in vitro Assessment of Oral Lipid Based Formulations. Adv Drug Deliv Rev 2001a; 50:S127–S147
Porter CJ and Charman WN. Lipid-based Formulations for Oral Administration: Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs. J Recept Signal Transduct Res 2001b; 21:215–257
Porter CJH, Charman SA, and Charman WN. Lymphatic Transport of Halofantrine in the Triple-cannulated Anesthetized Rat Model: Effect of Lipid Vehicle Dispersion. J Pharm Sci 1996a; 85:351–356
Porter CJH, Charman SA, Humberstone AJ, and Charman WN. Lymphatic Transport of Halofantrine in the Conscious Rat when Administered as either the Free Base or the Hydrochloride Salt: Effect of Lipid Class and Lipid Vehicle Dispersion. J Pharm Sci 1996b; 85:357–361
Sakai A, Mori N, Shuto S, and Suzuki T. Deacylation-reacylation Cycle: A Possible Absorption Mechanism for the Novel Lymphotropic Antitumor Agent Dipalmitoyl-phosphatidylfluorouridine in Rats. J Pharm Sci 1993; 82:575–583
Schoeller C, Keelan M, Mulvey G, Stremmel W, and Thomson AB. Oleic Acid Uptake into Rat and Rabit Jejunal Brush Border Membrane. Biochim Biophys Acta 1995a; 1236:51–64
Schoeller C, Keelan M, Mulvey G, Stremmel W, and Thomson AB. Role of a Brush Border Membrane Fatty Acid Binding Protein in Oleic Acid Uptake Into Rat and Rabbit Jejunal Brush Border Membrane. Clin Invest Med 1995b; 18:380–388
Scriba GK. Phenytoin-lipid Conjugates as Potential Prodrugs of Phenytoin. Arch Pharm (Weinheim) 1993a; 326:477–481
Scriba GK. Phenytoin-lipid Conjugates: Chemical, Plasma Esterase-Mediated, and Pancreatic Lipase-Mediated Hydrolysis in vitro. Pharm Res 1993b; 10:1181–1186
Scriba GK, Lambert DM, and Poupaert JH. Anticonvulsant Activity of Phenytoin-Lipid Conjugates, A New Class of Phenytoin Prodrugs. J Pharm Pharmacol 1995a; 47:197–203
Scriba GK, Lambert DM, and Poupaert JH. Bioavailability and Anticonvulsant Activity of a Monoglyceride-Derived Prodrug of Phenytoin after Oral Administration to Rats. J Pharm Sci 1995b; 84:300–302
Scriba GK, Lambert DM, and Poupaert JH. Bioavailability of Phenytoin Following Oral Administration of Phenytoin-Lipid Conjugates to Rats. J Pharm Pharmacol 1995c; 47:945–948
Shackleford DM, Faassen WA, Houwing N, Lass H, Edwards GA, Porter CJ, and Charman WN. Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone after Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-Cannulated Dogs. J Pharmacol Exp Ther 2003; 306:925–933
Shashoua VE, Jacob JN, Ridge R, Campbell A, and Baldessarini RJ. Gammaaminobutyric Acid Esters. 1. Synthesis, Brain Uptake, and Pharmacological Studies of Aliphatic and Steroid Esters of gamma-Aminobutyric Acid. J Med Chem 1984; 27:659–664
Sieber SM. The Lymphocytic Absorption of p, p′-DDT and Some Structurallyrelated Compounds in the Rat. Pharmacology 1976; 14:443–454
Stella VJ and Pochopin NL. Lipophilic Prodrugs and the Promotion of Intestinal Lymphatic Drug Transport. In: Charman W N and Stella V J. Lymphatic Transport of Drugs Boca Raton: CRC Press; 1992:181–210
Stremmel W. Uptake of Fatty Acids by Jejunal Mucosal Cells Is Mediated by a Fatty Acid Binding Membrane Protein. J Clin Invest 1988; 82:2001–2010
Stremmel W, Lotz G, Strohmeyer G, and Berk PD. Identification Isolation and Partial Characterization of a Fatty Acid Binding Protein from Rat Jejunal Microvillus Membranes. J Clin Invest 1985; 75:1068–1076
Sugihara J and Furuuchi S. Lymphatic Absorption of Hypolipidemic Compound, 1-O-[p-(myristyloxy)-alpha-methylcinnamoyl] Glycerol (LK-903). J Pharmacobiodyn 1988; 11:121–130
Sugihara J, Furuuchi S, Ando H, Takashima K, and Harigaya S. Studies on Intestinal Lymphatic Absorption of Drugs. II. Glyceride Prodrugs for Improving Lymphatic Absorption of Naproxen and Nicotinic Acid. J Pharmacobiodyn 1988; 11:555–562
Swartz MA. The Physiology of the Lymphatic System. Adv Drug Deliv Rev 2001; Aug 23; 50:3–20
Taillardat-Bertschinger A, Perry CS, Galland A, Prankerd RJ, and Chairman WN. Partitioning of Halofantrine Hydrochloride Between Water, Micellar Solutions, and Soybean Oil: Effects on Its Apparent Ionization Constant. J Pharm Sci 2003; 92:2217–2228
Thomson AB, Schoeller C, Keelan M, Smith L, and Clandinin MT. Lipid Absorption: Passing through the Unstirred Layers, Brush-Border Membrane, and Beyond. Can J Physiol Pharmacol 1993; 71:531–555
Ueda CT, Lemaire M, Gsell G, and Nussbaumer K. Intestinal Lymphatic Absorption of Cyclosporin A Following Oral Administration in an Olive Oil Solution to Rats. Biopharm Drug Dispos 1983; 4:113–124
Vyas SP, Jaitely V, and Kanaujia P. Synthesis and Characterisation of Palymitoyl Propanolol Hydrochloride Auto-Lymphotrophs for Oral Administration. Int J Pharm 1999; 186:177–189
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 American Association of Pharmaceutical Scientists
About this chapter
Cite this chapter
Shackleford, D.M., Porter, C.J.H., Charman, W.N. (2007). Lymphatic Absorption of Orally Administered Prodrugs. In: Stella, V.J., Borchardt, R.T., Hageman, M.J., Oliyai, R., Maag, H., Tilley, J.W. (eds) Prodrugs. Biotechnology: Pharmaceutical Aspects, vol V. Springer, New York, NY. https://doi.org/10.1007/978-0-387-49785-3_18
Download citation
DOI: https://doi.org/10.1007/978-0-387-49785-3_18
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-49782-2
Online ISBN: 978-0-387-49785-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)