新型溫感性高分子聚合物，於低溫下呈現液態，而在體溫環境下會凝聚成半固態的膠狀物。此類的高分子聚合物具有生物可相容及生物可分解之特性，而這樣公認為安全的素材，也應用於藥物製劑的組成中，一般用為賦型劑中的增稠劑或介面活性劑；近年來亦有許多學者嘗試利用此溫度敏感的性質，應用於藥品身體輸送系統上，做為局部給藥或為緩釋劑型。然而文獻上，曾指出兩性區塊型的溫感性高分子聚合物作用在數種具多重抗藥性相關蛋白 (MDR/MRP) 表現的細胞，能夠使一些原本具抗藥性之藥品產生敏感反應。
　　本研究以工研院研發合成的兩性區塊型溫感性高分子聚合物PEG/PLGA，藉由離體灌流大白鼠肝臟的模式，評估其應用為局部投藥劑型之效果，並在活體大白鼠之動物實驗中，探討其對藥品藥物動力學的影響；此外藉由臨床上已使用且同屬於兩性區塊型溫感性高分子聚合物Pluronic F-127，進一步探討這類聚合物對於老鼠肝臟Mdr/Mrp 輸送子的影響。
　　研究結果顯示，由國人研發合成之新型PEG/PLGA溫感性高分子聚合物，應用為局部藥物輸送系統之載體能有效地侷限藥物在局部給藥處，且可降低藥物暴露於系統性血液循環中；另一方面Pluronic F-127也在離體灌流老鼠肝臟及活體頸靜脈及膽道插管的動物實驗中，發現其可能會對體內MDR/MRP 輸送子產生抑制效應，而降低藥物的膽汁排除。
　　本研究結論為新型的PEG/PLGA溫感性高分子聚合物，能有效地應用於藥物局部輸送系統上，然而對於這類兩性區塊型聚合物不論用為臨床上藥物賦型劑或藥物輸送系統之載體，都應進一步的考量其可能有機會影響藥物於體內的動態情形，甚至引起藥物交互作用之可能。

　　Introduction. Novel thermosensitive copolymers with a specific composition are a free flowing sol at low temperature, but become a transparent semi-solid gel at body temperature and they can be both biodegradable and biocompatible. These safety materials have been applied to the formulation of pharmaceuticals, generally as the excipients or surfactants. In recent years, efforts have been made to try utilizing such thermosensitive characteristics on drug delivery system, local drug delivery or delay-release dosage forms. Noteablely, previous studies have demonstrated that some of the amphiphilic thermosensitive block copolymers can improve the transport of rhodamine, digoxin and danounrubcin…etc., across the MDR/MRP overexpression cell lines, such as Caco-2, Chinese hamster ovary cells, BBMECs, human ovarian carcinoma cells.
　　Purpose. The aim of this study was to evaluate the effects of thermosensitive biodegradable copolymer on drug delivery and transport.
Methods. A new PEG/PLGA amphiphilic thermosensitive block copolymer, developed and synthesized by the Industrial Technology Research Institute of Taiwan, was used to evaluate its local delivery effect for paclitaxel in the isolated perfused rat liver and for irinotecan in rats following intra-liver and intra-peritoneal administration, respectively. To investigate the effects of amphiphilic thermosensitive block copolymers on Mdr/Mrp transporters, the biliary secretion of ciprofloxacin and digoxin was characterized in the absence and presence of Pluronic F-127.
　　Results. The new PEG/PLGA copolymer showed favorable local delivery effects by limiting the anticancer drugs in the local tissues and reducing their systemic exposure. The biliary secretion of both ciprofloxacin and digoxin was significantly reduced by Pluronic F-127, suggesting an inhibitory effect of Pluronic F-127 on Mdr/Mrp transporters.
　　Conclusion. In summary, the new PEG/PLGA amphiphilic thermosensitive block copolymer from the Industrial Technology Research Institute of Taiwan can be used for local drug delivery. And Pluronic F-127 may alter drug dispositions through its inhibition on Mdr/Mrp transporters.

Alakhov VY, Moskaleva EY, Batrakova EV and Kabanov AV (1996) Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer. Bioconjug Chem 7:209-16.

Allwood MC and Martin HJ (1996) The extraaction of diethylhexylpthalate (DEHP) from polyvinylchloride components of intravenous infusion containers and administration sites by paclitaxel injection. Int J Pharm 127:65-71.

Attwood D, Collett, JH, Tait CJ (1985) The micellar properties of the poly(oxyethylene)-poly(oxypropylene) copolymer Pluronic F127 in water and electrolyte solution. Int J Pharm 26:25-33.

Balasubramanian SV, Alderfer JL and Straubinger RM (1994) Solvent- and concentration-dependent molecular interactions of taxol (Paclitaxel). J Pharm Sci 83:1470-76.

Barichello JM, Morishita M, Takayama K and Nagai T (1999) Absorption of insulin from pluronic F-127 gels following subcutaneous administration in rats. Int J Pharm 184:189-98.

Batrakova EV, Han HY, Alakhov VYu, Miller DW and Kabanov AV (1998a) Effects of pluronic block copolymers on drug absorption in caco-2 cell monolayers. Pharm Res 15: 850-55.

Batrakova EV, Han HY, Miller DW and Kabanov AV (1998b) Effects of pluronic P85 unimers and micelles on drug permeability in polarized BBMEC and caco-2 cells. Pharm Res 15:1525-32.

Batrakova EV, Li S, Alakhov VY, Elmquist WF, Miller DW and Kabanov AV (2003) Sensitization of cells overexpressing multidrug-resistant proteins by pluronic P85. Pharm Res 20:1581-90.

Batrakova EV, Li S, Elmquist WF, Miller DW, Alakhov VY and Kabanov AV (2001a) Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. Br J Cancer 85:1987-97.

Batrakova EV, Li S, Vinogradov SV, Alakhov VY, Miller DW and Kabanov AV (2001b) Mechanism of pluronic effect on P-glycoprotein efflux system in blood-brain barrier: contributions of energy depletion and membrane fluidization. J Pharmacol Exp Ther 299:483-93.

Batrakova EV, Miller DW, Li S, Alakhov VY, Kabanov AV and Elmquist WF (2001c) Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. J Pharmacol Exp Ther 296:551-57.

Bhardwaj R and Blanchard J (1996) Controlled release delivery system for the a-MSH analog melanotan-I using Poloxamer 407. J Pharm Sci 85:915-19.

Bittner B, Guenzi A, Fullhardt P, Zuercher G, Gonzalez RC and Mountfield RJ (2002) Improvement of the bioavailability of colchicine in rats by coadministration of alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid. Arzneim Forsch Drug Res 52:684-88.

Blonder JM, Baird L, Fulfs JC and Rosenthal GJ (1999) Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel. Life Sci 65:PL261-66.

Bogman K, Erne-Brand F, Alsenz J and Drewe J (2003) The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins. J Pharm Sci 92:1250-61.

Borst P and Schinkel AH (1997) Genetic dissection of the function of mammalian P-glycoproteins. Trends Genet 13:217-22.

Buchler M, Konig J, Brom M, Kartenbeck J, Spring H, Horie T and Keppler D (1996) cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J Biol Chem 271:15091-98.
Burris HA, 3rd and Fields SM (1994) Topoisomerase I inhibitors. An overview of the camptothecin analogs. Hematol Oncol Clin North Am 8:333-55.

Burris HA, Rothenberg ML, Kuhn JG and Von Hoff DD (1992) Clinical trials with the topoisomerase I inhibitors. Semin Oncol 19:663-69.

Cavet ME, West M and Simmons NL (1997) Fluoroquinolone (ciprofloxacin) secretion by human intestinal epithelial (Caco-2) cells. Br J Pharmacol 121:1567-78.

Chang T, Benet, LZ and Hebert, MF (1996) The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 59:297-03.

Cheng JWM, Charland SL and Shaw LM. (1997) Is the volume of distribution of digoxin reduced in patients with renal dysfunction? determining digoxin pharmacokinetics by fluorescence polarization immunoassay. Pharmacotherapy. 17: 584-90.

Chourpa I, Millot JM, Sockalingum GD, Riou JF and Manfait M (1998) Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy. Biochim Biophys Acta 1379:353-66.

Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM and Deeley RG (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258:1650-54.

Cordon-Cardo C, O'Brien JP, Boccia J, Casals D, Bertino JR and Melamed MR (1990) Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38:1277-87.

Cornaire G, Woodley J, Hermann P, Cloarec A, Arellano C and Houin G (2004) Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo. Int J Pharm 278:119-31.
Dautrey S, Felice K, Petiet A, Lacour B, Carbon C and Farinotti R (1999) Active intestinal elimination of ciprofloxacin in rats: modulation by different substrates. Br J Pharmacol 127:1728-34.

de Lange EC, Marchand S, van den Berg D, van der Sandt IC, de Boer AG, Delon A, Bouquet S and Couet W (2000) In vitro and in vivo investigations on fluoroquinolones; effects of the P-glycoprotein efflux transporter on brain distribution of sparfloxacin. Eur J Pharm Sci 12:85-93.

Dhanikula AB and Panchagnula R (1999) Localized paclitaxel delivery. Int J Pharm 183:85-100.

DiBiase MD and Rhodes CT (1996) Formulation and evaluation of epidermal growth factor in pluronic F-127 gel. Drug Dev Ind Pharm 22:823-31.

Dintaman JM and Silverman JA (1999) Inhibition of P-glycoprotein by -alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res 16:1550-56.

Dustin P (1980) Microtubules. Sci Am 243:66-76.

Escoriaza J, Aldaz A, Castellanos C, Calvo E and Giraldez J (2000) Simple and rapid determination of irinotecan and its metabolite SN-38 in plasma by high-performance liquid-chromatography: application to clinical pharmacokinetic studies. J Chromatogr B 740:159-68.

Ewy GA, Groves BM and Ball MF (1971) Digoxin metabolism in obesity. Circulation. 44: 810-14.

Fojo A, Akiyama S, Gottesman MM and Pastan I (1985) Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res 45:3002-07.

Friedland D, Gorman G and Treat J (1993) Hypersensitivity reactions from taxol and etoposide. J Natl Cancer Inst 85:2036.

Fults KA and Johnston TP (1989) Sustained release of urease from a Poloxamer gel matrix. J Parent Sci Technol 44:58-65.

Gallo RC, Whang-Peng J and Adamson RH (1971) Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Natl Cancer Inst 46:789-95.

Gilbert JC, Richardson, J.L., Davies, M.C., Palin, K.J., Hadgraft, J. (1987) The effect of solutes and polymers on the gelation properties of Pluronic F-127 solutions for controlled drug delivdery. J Control Release 5:113-18.

Gonzalez MA, Moranchel AH, Duran S, Pichardo A, Magana JL, Painter B, Forrest A and Drusano GL (1985) Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers. Antimicrob Agents Chemother 28:235-39.

Gonzalez MA, Uribe F, Moisen SD, Fuster AP, Selen A, Welling PG and Painter B (1984) Multiple-dose pharmacokinetics and safety of ciprofloxacin in normal volunteers. Antimicrob Agents Chemother 26:741-44.

Hall WH & Doherty JE (1971) Tritiated digoxin. XVI. gastric absorption. Am J Dig Dis. 16: 903-08.

Hatefi A and Amsden B (2002) Biodegradable injectable in situ forming drug delivery systems. J Control Release 80:9-28.

Higgins CF and Gottesman MM (1992) Is the multidrug transporter a flippase? Trends Biochem Sci 17:18-21.

Hoffken G, Lode H, Prinzing C, Borner K and Koeppe P (1985) Pharmacokinetics of ciprofloxacin after oral and parenteral administration. Antimicrob Agents Chemother 27:375-79.

Hoffman AS (1995) "Intelligent" polymers in medicine and biotechnology. Artif Organs 19:458-67.

Hooiveld GJ, van Montfoort JE, Meijer DK and Muller M (2001) Function and regulation of ATP-binding cassette transport proteins involved in hepatobiliary transport. Eur J Pharm Sci 12:525-43.

Hori R, Okamura N, Aiba T and Tanigawara Y (1993) Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. J Pharmacol Exp Ther 266:1620-25.

Howrie DL, Ptachcinski RJ, Griffith BP, Hardesty RJ, Rosenthal JT, Burckart GJ and Venkataramanan R (1985) Anaphylactoid reactions associated with parenteral cyclosporine use: possible role of Cremophor EL. Drug Intell Clin Pharm 19:425-27.

Hsiang YH, Hertzberg R, Hecht S and Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873-78.

Hyde SC, Emsley P, Hartshorn MJ, Mimmack MM, Gileadi U, Pearce SR, Gallagher MP, Gill DR, Hubbard RE and Higgins CF (1990) Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature 346:362-65.

Iisalo E (1977) Clinical pharmacokinetics of digoxin. Clin. pharmacokinet. 2: 1-16.

Ito K, Suzuki H, Hirohashi T, Kume K, Shimizu T and Sugiyama Y (1997) Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR. Am J Physiol 272:G16-22.

Jamis-Dow CA, Klecker RW, Katki AG and Collins JM (1995) Metabolism of taxol by human and rat liver in vitro: a screen for drug interactions and interspecies differences. Cancer Chemother Pharmacol 36:107-14.

Jeong B, Bae YH and Kim SW (1999) Thermoreversible gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions. Macromolecules 32:7064-69.

Jeong B, Bae YH and Kim SW (2000a) In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. J Biomed Mater Res 50:171-77.

Jeong B, Bae YH, Lee DS and Kim SW (1997) Biodegradable block copolymers as injectable drug-delivery systems. Nature 388:860-62.

Jeong B, Kibbey MR, Birnbaum JC, Won YY and Gutowska A (2000b) Thermogelling biodegradable polymers with hydrophilic backbones: PEG-g-PLGA. Macromolecules 33:8317-22.

Jeong B, Kim SW and Bae YH (2002) Thermosensitive sol-gel reversible hydrogels. Adv Drug Deliv Rev 54:37-51.

Jorgensen EB, Hvidt S, Brown W and Schilen K (1997) Effect of salts on the micellization and gelation of a triblock copolymer studied by rheology and light scattering. Macromolecules 30:2355-64.

Juliano RL and Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152-62.

Kano Y, Suzuki K, Akutsu M, Suda K, Inoue Y, Yoshida M, Sakamoto S and Miura Y (1992) Effects of CPT-11 in combination with other anti-cancer agents in culture. Int J Cancer 50:604-10.

Kartenbeck J, Leuschner U, Mayer R and Keppler D (1996) Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061-66.

Kawato Y, Aonuma M, Hirota Y, Kuga H and Sato K (1991) Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor effect of CPT-11. Cancer Res 51:4187-91.

Keppler D and Konig J (1997) Hepatic canalicular membrane 5: Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. Faseb J 11:509-16.

Kim YJ, Choi S, Koh JJ, Lee M, Ko KS and Kim SW (2001) Controlled release of insulin from biodegradable triblock copolymer. Pharm Res 18:548-50.

Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, Jansen G, Peters GJ, Ponne N, Scheper RJ, Elferink RP, Baas F and Borst P (1999) MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A 96:6914-19.

Koopen NR, Wolters H, Havinga R, Vonk RJ, Jansen PL, Muller M and Kuipers F (1998) Impaired activity of the bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat. Hepatology 27:537-45.

Kusuhara H and Sugiyama Y (2002) Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J Control Release 78:43-54.

Lau YY, Wu CY, Okochi H and Benet LZ (2004) Ex situ inhibition of hepatic uptake and efflux significantly changes metabolism: hepatic enzyme-transporter interplay. J Pharmacol Exp Ther 308:1040-45.

Lesher GY, Froelich EJ, Gruett MD, Bailey JH and Brundage RP (1962) 1,8-Naphthyridine Derivatives. A New Class of Chemotherapeutic Agents. J Med Pharm Chem 91:1063-65.

Li RC, Nix DE and Schentag JJ (1994) Interaction between ciprofloxacin and metal cations: its influence on physicochemical characteristics and antibacterial activity. Pharm Res 11:917-20.

Lilley LL and Scott HB (1993) What you need to know about Taxol. Am J Nurs 93:46-50.

Lin HR and Sung KC (2000) Carbopol/pluronic phase change solutions for ophthalmic drug delivery. J Control Release 69:379-88.

Lokiec F, Canal P, Gay C, Chatelut E, Armand JP, Roche H, Bugat R, Goncalves E and Mathieu-Boue A (1995) Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine. Cancer Chemother Pharmacol 36:79-82.

Longnecker SM, Donehower RC, Cates AE, Chen TL, Brundrett RB, Grochow LB, Ettinger DS and Colvin M (1987) High-performance liquid chromatographic assay for taxol in human plasma and urine and pharmacokinetics in a phase I trial. Cancer Treat Rep 71:53-59.

Loo TW and Clarke DM (1994) Reconstitution of drug-stimulated ATPase activity following co-expression of each half of human P-glycoprotein as separate polypeptides. J Biol Chem 269:7750-55.

Lowes S and Simmons NL (2002) Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco-2) cells. Br J Pharmacol 135:1263-75.

Lu GW, Jun HW, Dzimianski MT, Qiu HC and McCall JW (1995) Pharmacokinetic studies of methotrexate in plasma and synovial fluid following i.v. bolus and topical routes of administration in dogs. Pharm Res 12:1474-77.

Lum BL, Fisher GA, Brophy NA, Yahanda AM, Adler KM, Kaubisch S, Halsey J and Sikic BI (1993) Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. Cancer 72:3502-14.

Lundberg BB (1997) A submicron lipid emulsion coated with amphipathic polyethylene glycol for parenteral administration of paclitaxel (Taxol). J Pharm Pharmacol 49:16-21.

Madhu C, Gregus Z and Klaassen CD (1989) Biliary excretion of acetaminophen-glutathione as an index of toxic activation of acetaminophen: effect of chemicals that alter acetaminophen hepatotoxicity. J Pharmacol Exp Ther 248:1069-77.

Malmsten M and Lindman B (1992) Self-assembly in aqueous block copolymer solution. Macromolecules 25:5446-50.
Manfredi JJ and Horwitz SB (1984) Taxol: an antimitotic agent with a new mechanism of action. Pharmacol Ther 25:83-125.

Masuda M, I'Izuka Y, Yamazaki M, Nishigaki R, Kato Y, Ni'inuma K, Suzuki H and Sugiyama Y (1997) Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res 57:3506-10.

Mathew AE, Mejillano MR, Nath JP, Himes RH and Stella VJ (1992) Synthesis and evaluation of some water-soluble prodrugs and derivatives of taxol with antitumor activity. J Med Chem 35:145-51.

Mayer R, Kartenbeck J, Buchler M, Jedlitschky G, Leier I and Keppler D (1995) Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. J Cell Biol 131:137-50.

Michot JM, Van Bambeke F, Mingeot-Leclercq MP and Tulkens PM (2004) Active efflux of ciprofloxacin from J774 macrophages through an MRP-like transporter. Antimicrob Agents Chemother 48:2673-82.

Miller DW, Batrakova EV and Kabanov AV (1999) Inhibition of multidrug resistance-associated protein (MRP) functional activity with pluronic block copolymers. Pharm Res 16:396-01.

Morishita M, Barichello JM, Takayama K, Chiba Y, Tokiwa S and Nagai T (2001) Pluronic F-127 gels incorporating highly purified unsaturated fatty acids for buccal delivery of insulin. Int J Pharm 212:289-93.

Mottino AD, Hoffman T, Jennes L and Vore M (2000) Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J Pharmacol Exp Ther 293:717-23.

Mu L and Feng SS (2003) A novel controlled release formulation for the anticancer drug paclitaxel (Taxol®): PLGA nanoparticles containing vitamin E TPGS. J Control Release 86:33-48.

Nightingale SL (1992) From the Food and Drug Administration. JAMA 268:1390.

Nishida K, Tonegawa C, Kautani T, Hashida M and Sezaki H (1989) Statistical moment analysis of hepatobiliary transport of phenol red in the perfused rat liver. Pharm Res 6:140-46.

Nivedita K, Pandit, Justin K. (1996) Loss of gelatin ability of pluronic F127 in the presence of some salts. Int J Pharm 145:129-36.

Nix DE and DeVito JM (1987) Ciprofloxacin and norfloxacin, two fluoroquinolone antimicrobials. Clin Pharm 6:105-17.

Nix DE, Watson WA, Lener ME, Frost RW, Krol G, Goldstein H, Lettieri J and Schentag JJ (1989) Effects of aluminum and magnesium antacids and ranitidine on the absorption of ciprofloxacin. Clin Pharmacol Ther 46:700-05.

O'Dwyer PJ, King SA, Fortner CL and Leyland-Jones B (1986) Hypersensitivity reactions to teniposide (VM-26): an analysis. J Clin Oncol 4:1262-69.

Oude Elferink RP, Meijer DK, Kuipers F, Jansen PL, Groen AK and Groothuis GM (1995) Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim Biophys Acta 1241:215-68.

Palmer WK, Emeson EE and Johnston TP (1998) Poloxamer 407-induced atherogenesis in the C57BL/6 mouse. Atherosclerosis 136:115-23.

Paradis D, Vallee F, Allard S, Bisson C, Daviau N, Drapeau C, Auger F and LeBel M (1992) Comparative study of pharmacokinetics and serum bactericidal activities of cefpirome, ceftazidime, ceftriaxone, imipenem, and ciprofloxacin. Antimicrob Agents Chemother 36:2085-92.

Paulusma CC, Bosma PJ, Zaman GJ, Bakker CT, Otter M, Scheffer GL, Scheper RJ, Borst P and Oude Elferink RP (1996) Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271:1126-28.

Pizzolato JF and Saltz LB (2003) The camptothecins. Lancet 361:2235-42.

Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC and Piwnica-Worms D (1999) Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 96:3900-05.

Rassing J and Attwood D (1983) Ultrasound velocity and light scattering studies on the polyoxyethylene?polyoxypropylene copolymer Pluronic F127 in aqueous solution. Int J Pharm 13:47-55.

Rassing J, Mckenna W, Bandyopadhyay S and Eyring E (1984) Ultrasonic and 13C-NMR studies on gel formation in aqueous solution of ABA block copolymeric Pluronic F-127. J Mol Liq 27:165-78

Ringel I and Horwitz SB (1991) Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 83:288-91.

Robert J (1999) Multidrug resistance in oncology: diagnostic and therapeutic approaches. Eur J Clin Invest 29:536-45.

Roberts MS, Magnusson BM, Burczynski FJ and Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41:751-90.

Rodriguez-Ibanez M, Nalda-Molina R, Montalar-Montero M, Bermejo MV, Merino V and Garrigues TM (2003) Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies. Eur J Pharm Biopharm 55:241-46.

Rohwedder R, Bergan T, Thorsteinsson SB and Scholl H (1990) Transintestinal elimination of ciprofloxacin. Chemotherapy 36:77-84.

Rost D, Konig J, Weiss G, Klar E, Stremmel W and Keppler D (2001) Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia. Gastroenterology 121:1203-08.

Rothenberg ML, Kuhn JG, Burris HA, 3rd, Nelson J, Eckardt JR, Tristan-Morales M, Hilsenbeck SG, Weiss GR, Smith LS, Rodriguez GI and et al. (1993) Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194-04.

Rowinsky EK, Cazenave LA and Donehower RC (1990) Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst 82:1247-59.

Rowinsky EK and Donehower RC (1993) The clinical pharmacology of paclitaxel (Taxol). Semin Oncol 20:16-25.

Rowinsky EK and Donehower RC (1995) Paclitaxel (taxol). N Engl J Med 332:1004-14.

Schaub TP, Kartenbeck J, Konig J, Vogel O, Witzgall R, Kriz W and Keppler D (1997) Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules. J Am Soc Nephrol 8:1213-21.

Schiff PB, Fant J and Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277:665-67.

Seral C, Carryn S, Tulkens PM and Van Bambeke F (2003) Influence of P-glycoprotein and MRP efflux pump inhibitors on the intracellular activity of azithromycin and ciprofloxacin in macrophages infected by Listeria monocytogenes or Staphylococcus aureus. J Antimicrob Chemother 51:1167-73.

Shono Y, Nishihara H, Matsuda Y, Furukawa S, Okada N, Fujita T and Yamamoto A (2004) Modulation of intestinal P-glycoprotein function by cremophor EL and other surfactants by an in vitro diffusion chamber method using the isolated rat intestinal membranes. J Pharm Sci. 93:877-85.

Slichenmyer WJ, Rowinsky EK, Donehower RC and Kaufmann SH (1993) The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85:271-91.

Slichenmyer WJ and Von Hoff DD (1990) New natural products in cancer chemotherapy. J Clin Pharmacol 30:770-88.

Song MJ, Lee DS, Ahn JH, Kim DJ and Kim SC (2000) Dielectric behavior during sol-gel transition of PEO-PPO-PEO triblock copolymer aqueous solution. Polymer Bulletin 43:497-04.

Sorgel F, Naber KG, Jaehde U, Reiter A, Seelmann R and Sigl G (1989) Gastrointestinal secretion of ciprofloxacin. Evaluation of the charcoal model for investigations in healthy volunteers. Am J Med 87:62S-65S.

Strelevitz TJ and Linhares MC (1996) Simultaneous determination of danofloxacin and N-desmethyldanofloxacin in cattle and chicken edible tissues by liquid chromatography with fluorescence detection. J Chromatogr B 675:243-50.

Suzuki H and Sugiyama Y (1998) Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2. Semin Liver Dis 18:359-76.

Tanigawara Y (2000) Role of P-glycoprotein in drug disposition. Ther Drug Monit 22:137-40.

Taniguchi K, Wada M, Kohno K, Nakamura T, Kawabe T, Kawakami M, Kagotani K, Okumura K, Akiyama S and Kuwano M (1996) A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res 56:4124-29.

Teixeira MH, Vilas-Boas LF, Gil VM and Teixeira F (1995) Complexes of ciprofloxacin with metal ions contained in antacid drugs. J Chemother 7:126-32.

Tsujii H, Konig J, Rost D, Stockel B, Leuschner U and Keppler D (1999) Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 117:653-60.

Ueda K, Yoshida A and Amachi T (1999) Recent progress in P-glycoprotein research. Anticancer Drug Des 14:115-21.

Urbatsch IL, Sankaran B, Bhagat S and Senior AE (1995) Both P-glycoprotein nucleotide-binding sites are catalytically active. J Biol Chem 270:26956-61.

Venne A, Li S, Mandeville R, Kabanov A and Alakhov V (1996) Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. Cancer Res 56:3626-29.

Wall ME, Wani MC, Cook CE, Palmer KH and McPahil AT (1966) Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 88:3888.

Wani MC, Taylor HL, Wall ME, Coggon P and McPhail AT (1971) Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93:2325-27.

Wanka G, Hoffmann H and Ulbricht W (1990) The aggregation behavior of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) block copolymers in aqueous solution. Colloid Polym. Sci. 268:101-17.

Wasan KM, Subramanian R, Kwong M, Goldberg IJ, Wright T and Johnston TP (2003) Poloxamer 407-mediated alterations in the activities of enzymes regulating lipid metabolism in rats. J Pharm Pharm Sci 6:189-97.

Waugh WN, Trissel LA and Stella VJ (1991) Stability, compatibility, and plasticizer extraction of taxol (NSC-125973) injection diluted in infusion solutions and stored in various containers. Am J Hosp Pharm 48:1520-24.
Weiss J, Tayler GR, Zimmermann F and Nebendabl K (2000) Collection of body fluids, in The Handbook of Experimental Animals-The Laboratory Rat. (Krinke GJ ed), Academic Press, New York. p.485-510

Weiss RB, Donehower RC, Wiernik PH, Ohnuma T, Gralla RJ, Trump DL, Baker JR, Jr., Van Echo DA, Von Hoff DD and Leyland-Jones B (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8:1263-68.

Wier WG and Hess P (1984) Excitation-contraction coupling in cardiac Purkinje fibers. Effects of cardiotonic steroids on the intracellular [Ca2+] transient, membrane potential, and contraction. J. Genet. Psychol. 83: 395- 415.

Withering W (1941) An account of the foxglove and some of its medical uses, with practical remarks on dropsy, and other diseases, in Classics of Cardiology, Vol 1. (Willins FA and Keys TE eds), Henry Schuman, Dover Publications, New York. p. 231-52

Yamazaki M, Suzuki H and Sugiyama Y (1996) Recent advances in carrier-mediated hepatic uptake and biliary excretion of xenobiotics. Pharm Res 13:497-513.

Yamazaki TS, Hanai Y, Mochimaru M, Tsujino J, Sawada I, Horie UT. (2000) Non-ionic detergent Tween 80 modulates VP-16 resistance in classical multidrug resistant K562 cells via enhancement of VP-16 influx. Cancer Lett. 149:153-61.

Yu GE, Deng Y, Dalton S, Wang QG, Attwood G, Price C and Booth C (1992) Micellization and gelation of triblock copoly(oxyethylene/oxypropylene/oxy
-ethylene), F-127. J Chem Soc, Faraday Trans 88:2537-44.

Yu L, Bridgers A, Polli J, Vickers A, Long S, Roy A, Winnike R and Coffin M (1999) Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. J Phar Sci 16:1812-17.

Zentner GM, Rathi R, Shih C, McRea JC, Seo MH, Oh H, Rhee BG, Mestecky J, Moldoveanu Z, Morgan M and Weiman S (2001) Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J Controlled Release 72:203-15.

Zhang K and Khan A (1995) Phase behavior of poly(ethylene oxide)-poly(propylene oxide) triblock copolymers in water. Macromolecules 28:3807-12.