Note: OATP: organic anion-transporting polypeptide; OAT: organic anion transporter; OCT: organic cation transporter.

Organic Anion Transporter (OAT)

Human OATs play important roles especially in the elimination of a variety of endogenous substances, drugs, and their metabolites from the liver and kidney. So far, five OAT members have been identified [39-43]. Structurally, OATs are membrane proteins with 12 putative membrane-spanning domains and function as sodium-independent exchangers or facilitators [44]. OATs are multispecific organic anion transporters, the substrates of which include both endogenous (e.g., cyclic nucleotides, prostaglandins, urate, dicarboxylates) and a wide variety of clinically important anionic drugs, such as ^-lactam antibiotics, diuretics, NSAIDs, anti-HIV therapeutics, anti-tumor drugs, and angiotensin-converting enzyme inhibitors [45-48]. The most commonly used model substrate for OAT studies is paraaminohippuric acid (PAH). Therefore, the OAT system has alternatively been called the PAH transport system. All members of the OAT family are expressed in the kidney, while only some are expressed in the liver, brain, and placenta [49-51]. The OAT family represents the renal secretory pathway for organic anions and is also involved in the distribution of organic anions in the body [52]. OAT-K1, together with MRP2 and OATP1, may contribute to the efflux of organic anions into luminal side of renal proximal tubules. OAT-K1 is a Na+-dependent transporter system, whereas OAT2, OAT3, and OAT4 are Na+-independent transporters, whose function is to uptake organic anions into cells [53]. OATs may play a role in drug interactions as well. It has been reported that concurrent use of methotrexate with acidic drugs, such as NSAIDs, ^-lactam antibiotics, causes severe suppression of bone marrow, which seems to be related to the competitive inhibition of the renal OAT system [54].

Organic Cation Transporters (OCT)

Three members of OCT have been reported. OCT1, OCT2, and OCT3 transporters are electrogenic, Na+-independent, and pH-independent facilitated diffusion systems responsible for the uptake of organic cations into the cells [55]. In small intestine, liver, and segments of rat kidney proximal tubules, OCT1 is localized in the basolateral membranes of polarized epithelial cells [56]. The expression of OCT2 is more tissuespecific. Human OCT2 is detected mainly in the kidney with some expressed in brain and small intestines [57-59]. Human OCT2 in brain may help to reduce the background concentration of basic neurotransmitters and their metabolites [60].


The tissue distribution of transporters has been studied using different techniques. Consistent with their potential role in detoxification processes and physiological functions, transporters are expressed in various tissues as demonstrated in human normal tissues as well as in human cancer cell lines. Certain transporters show a more restricted tissue expression pattern (MDR3, BSEP, OATP-A, OATP-C, and OATP8) while others can be detected in almost every tissue that has been investigated (e.g., MDR1, OATP-B, OATP-D, and OATP-E). This indicates that some transporters have organ-specific functions while others might be involved in more housekeeping functions.


P-gp is expressed in the luminal membrane of intestinal mucosal epithelium. Several efflux pumps such as BCRP, MRP2, and MRP4 are also highly expressed in the intestinal mucosal epithelial cells. However, some of MRPs are expressed at basolateral membrane of intestinal epithelium, such as MRP1, MRP3, and MRP5 (Fig. 1). The abundance of P-gp expression varies in different intestinal sections. The expression of P-gp increases with distance. (The lowest amount of P-gp is located in stomach, highest in colon, and medium in jejunum/ileum [61], exactly opposite to the expression of CYP3A4/5.) CYP3A4/5 expression decreases longitudinally [62].

FIGURE 1 Schematic representation of selected ABC transporters in the intestinal membrane.


Liver is an important organ for metabolism of numerous endogenous and exogenous compounds, a process in which many transporters are involved. Hepatic uptake of organic anions, cations, and bile salts is supported by transporters in the basolateral (sinusoidal) membranes of hepatocytes including OATPs, OATs, and OCTs. ATP-binding cassette transporter proteins in the canalicular membranes of hepatocytes mediate the hepatic efflux of drugs, bile salts, and metabolites against a steep concentration gradient from liver to bile, which includes the MDR1 and MDR3, MRP2, and BSEP. However, MDR3 is mainly responsible for the transport of endogenous phospholipids though a recent report indicated that MDR3 may transport some drugs [63]. These transporters play essential roles in transporting, metabolizing, and excretion of bile salts, xenobiotics, and environmental toxins (Fig. 2).


Multiple organic anion transporters play important roles in the elimination of a variety of endogenous and exogenous compounds, and their metabolites from the body. Several families of multispecific organic anion transporters mediating the renal elimination of organic anions have been identified. Members of the organic anion transporter (OAT), organic anion transporting polypeptide (OATP), multidrug resistance protein (MRP),

FIGURE 2 Schematic representation of selected drug transporters in hepatocytes.

sodium-phosphate transporter (NPT), and peptide transporter (PEPT) families have been identified in the renal proximal tubules. Uptake of organic anions (OA-) across the basolateral membranes of renal epithelial cells followed by efflux into urine across the apical membrane is mediated by the Na+-dependent organic transporter, OAT1 and the Na+-independent organic transporter, perhaps OAT3. The function of MRP6 at the basolateral membrane is unknown. Efflux across the apical membrane of organic anions is through low-affinity anion exchange and/or facilitated diffusion, and a Na+-independent ATP-driven system. The luminal membrane contains various efflux transporter proteins including OATK1/ K2, OAT4, NPT, MRP2, and MRP4. The luminal membrane also contains various uptake transporters such as OATP1, PEPT 1/2 (Fig. 3).


The brain is protected against drugs and toxins by the two drug-permeability barriers: the BBB and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). The BBB is primarily formed by the endothelium of the blood capillaries in the brain. P-gp is expressed in the luminal plasma membrane of capillary endothelial cells and plays a significant role in restricting the brain permeability of drugs [64].

FIGURE 3 Schematic representation of selected renal drug transporters.

P-gp is expressed to a great extent in the apical (luminal) plasma membranes of these capillary endothelial cells, conferring an apical-to-basal transepithelial permeation barrier to drugs. MRP1 localizes basolaterally, conferring an opposing basal-to-apical drug-permeation barrier. Together, these transporter proteins may coordinate secretion and reabsorption of endogenous substrates and therapeutic drugs into and out of the central nervous system [65].

Recently, some other transporter proteins including MRPs, OATP, and OAT have been also reported to exist in the BBB and the BCFSB [66, 67].


P-gp is expressed at the brush border membrane of the syncytiotrophoblast. The expression appears to be higher early in gestation compared with term placenta [68, 69]. Absence or pharmacological inhibition of placental P-gp profoundly increases fetal drug exposure. Intravenous administration of radioactive digoxin, saquinavir, and paclitaxel to pregnant dams resulted in 2.4-, 7-, or 16-fold more drug in fetuses with mdrla (-/-)(-/-) 1b (-/-)(-/-) than the wild-type fetuses. Placental P-gp could be completely inhibited by PSC833 or GG918 when given to heterozygous dams indicating that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds, and demonstrate that this P-gp function can be abolished by pharmacological means [70].

The mRNA levels of various transporters in rat placenta were assessed during late-stage pregnancy. Sixteen mRNAs of various transporters were expressed in placenta at concentrations similar to or higher than that in maternal liver and kidney. They include Mdrla and 1b, Mrpl, Mrp5, Oct3 and Octn1, Oatp3, and oatp 12 [71]. The abundance of these mRNA transcripts in placenta suggests a role for these transporters in placental transport of endogenous and exogenous compounds. In human placenta, OATP-B has been detected in the trophoblast at the basal membranes where it may play a role in transporting natural substrates (e.g., steroid hormone conjugates) from the fetal circulation into the trophoblast [72].


P-glycoprotein is the product of multidrug resistance gene family, MDR1 and MDR3. P-gp encoded by MDR3 is expressed at the canalicular membrane of hepatocytes and is responsible for transporting phospholipids into bile ductules although a recent report has indicated that it may also transport some drugs. P-gp, MDR1 product, is expressed in many normal tissues including intestines, liver, brain, placenta, and testis though it was first discovered from cancer cells as a multidrug resistance protein. P-gp acts as an efflux pump by translocating substrates from the intracellular to the extracellular compartment.

Substrates, Inhibitors, and Inducers

P-gp has an ability to transport drugs diverse in chemical structure from different therapeutic classes (Table 1). Another striking feature is an overlap in substrates between P-gp and CYP3A4/5. These two substrate-sharing systems may serve as protective physiological barriers to limit harmful exposure to exogenous compounds.

Pharmacokinetic Implication

The high expression of P-gp in many tissues has made P-gp an additional physiological barrier to protect the body from the exposure to toxins and xenobiotics. Numerous studies have shown that P-gp plays an important role in the fate of absorption, distribution, metabolism, and excretion of drugs.

P-gp was first detected in certain cancer cells associated with the phenomenon of multiple drug resistance (MDR). However, it is now known that P-gp is highly expressed in normal tissues. In fact, P-gp is located in the apical domain of the enterocyte of the lower gastro-intestinal tract (jejunum, duodenum, ileum, and colon), thereby limiting the absorption of drug substrates from the gastro-intestinal tract. In other organs such as the liver and kidney, expression of this transporter at the apical membrane of hepatocytes and proximal tubular cells in kidney results in enhanced excretion of drug substrates into bile and urine respectively. P-gp is an important component in the BBB, limiting the CNS entry of a variety of drug substrates. P-gp is also found in other tissues known to have tissue-blood barriers, such as placenta and testis.


Drug absorption is a collective result from passive diffusion across intestinal membranes down a concentration gradient, intestinal metabolism, and P-gp efflux from the epithelial cells into the intestinal lumen. The effect of P-gp on drug absorption has been demonstrated using Mdr knockout mice and studies with P-gp inhibitors. Many clinically significant drug interactions are due to the inhibition of P-gp in the intestines.

After intravenous and oral administration of paclitaxel, the AUC was twofold and sixfold higher in Mdrla (-/-) mice compared to the wild-type

(wt) mice. Oral bioavailability of paclitaxel in Mdrla (-/-) and wt mice was 35% and 11% respectively. Biliary excretion of the drug was not different between the two groups of mice. After oral administration, 87 and 2% of the dose were found in the feces as paclitaxel in wt and mdrl a (-/-) mice suggesting substantial change in the extent of absorption of the drug when the effect of P-gp is removed [73].

Oral absorption of paclitaxel was increased when wt mice were cotreated with P-gp inhibitors, cyclosporine, or SDZ PSC 833. The oral AUC of paclitaxel was dramatically increased from 735 to 8066ng.h/ml when PSC833 was administered [74]. Concurrent drug therapy of P-gp inducers may decrease drug absorption. After two weeks of treatment with rifampin, the AUC of a single oral dose of digoxin was significantly reduced, due to the induction of intestinal P-gp [75].


As indicated earlier, the blood, brain, and the placental barriers are obstacles for a drug to reach the privileged compartments of the brain and the fetus.

After intravenous administration of digoxin and cyclosporine to Mdrla (-/-)(-/-) and wt mice, the ratio, (-/-):(+/+), of brain concentrations of digoxin and cyclosporine in these mice was about 35 and 17, while the plasma concentration ratio was only 1.9 and 1.4 respectively. Thus, mice without P-gp have increased concentrations of digoxin and cyclosporine in the brain [76].

Modulation of P-gp may result in an increase in the CSF levels of the protease inhibitors and this may have clinical implications. The disposition of protease inhibitors, indinavir, nelfinavir, and saquinavir was studied in Mdrla (-/-) and wt mice. Labeled compounds were administered intravenously and orally. After IV administration, there was no significant difference in plasma concentrations of total radioactivity at 4h, but the brain concentrations were considerably elevated in the Mdrla (-/-) mice. The brain concentration to plasma concentration ratio was the highest for nelfinavir and lowest for indinavir and saquinavir. After oral administration, radioactivity in the plasma was higher at 4 h in Mdrla (-/-) mice for all the three drugs [77]. The efflux of protease inhibitors from the brain in wt mice can be inhibited by the P-gp inhibitor, LY335959 [78]. OC144-093, a novel, extremely potent inhibitor of P-gp, does not inhibit multidrug resistance-associated protein (MRP1). This compound is not metabolized by cytochrome P4503A4, 2C. The enhancement of BBB penetration of antiepileptic drugs (AEDs) can be achieved with coadministration of 0C144-093 [79]. The presence of P-gp in the placenta limits fetal exposure to several compounds, but inhibition of P-gp can enhance the fetus concentrations of protease inhibitors and consequently may aid in the protection of the fetus from HIV infection.


Cytochrome P450s are expressed in the luminal membranes of intestines. These CYP enzymes are mainly CYP3A4/5 [62, 80-83]. The co-expression of P-gp and CYP3A4/5 and the interplay between P-gp and CYP3A4/5 in enterocytes result in longer residence time in enterocytes for drugs, potentially resulting in reduced bioavailability of certain drugs [84]. Since Pgp and CYP3A4/5 share common inducers, such as rifampicin and St. John's wort [85], increased expression of both systems may result in reduced bioavailability of certain therapeutic agents.


As described previously, P-gp is highly expressed in the hepatic bile canalicular membrane and renal proximal tubule luminal membrane. Inhibition of P-gp may result in changes in biliary excretion or renal proximal tubule excretion or both, depending on pharmacokinetic characteristics of the individual drug.

Digoxin is mainly eliminated by the kidney (~60%) and the rest by biliary secretion. Its renal clearance is greater than the filtration clearance indicating secretion of the drug by the kidney tubules. Kidney epithelial cell lines expressing human MDRI transport digoxin from basal to the apical membrane, and this transport is inhibited by cyclosporine [86]. In another cell line expressing MDRI, the potency of inhibition by the azoles decreased from itraconazole > ketoconazole >fluconazole [87]. A concomitant use of itraconazole increases the serum concentrations of digoxin. In a study with ten healthy volunteers, either 200 mg itraconazole or placebo was given orally once a day for five days. On day 3, each volunteer ingested a single 0.5-mg oral dose of digoxin. Digoxin AUC (0-72) was approximately 50% higher during the itraconazole phase than during the placebo phase. The renal clearance of digoxin was decreased by about 20% (P<0.01) by itraconazole. The decreased renal clearance of digoxin during the itraconazole phase may explain increased concentrations of digoxin during their concomitant use due to the inhibition of P-gp-mediated digoxin secretion in the renal tubular cells [88].

The effects of quinine and quinidine on the biliary and renal clearances of digoxin were investigated in healthy subjects. Digoxin was given alone and with concomitant administration of quinine or quinidine. Quinine and quinidine markedly reduced the steady-state biliary clearance of digoxin by about 35 and 42% respectively, while the steady-state renal clearance of digoxin was reduced significantly only by quinidine (29%) [89]. In a study of the effect of verapamil on the steady-state digoxin plasma concentrations, biliary and renal clearance of digoxin, the steady state concentration of digoxin was increased by 44%, and biliary clearance of digoxin was decreased by 43%, but renal clearance was unaffected, which may indicate that similar to quinine, verapamil only inhibits the transporters of biliary system [90].

Genetic Polymorphism

Although the genetic polymorphism of human MDR1 gene has been reported since late 1980s [91, 92], the impact of MDR1 genetic polymorphism on drug pharmacokinetics was highly contraversial. Hoffmeyer et al. conducted a systemic screening for MDR1 polymorphism and detected 15 single nucleotide polymorphisms (SNPs). An SNP in exon 26 of the MDR1 gene, C3435T (a silent mutation with no amino acid change), was correlated with P-gp protein levels and digoxin plasma concentrations after oral administration of the drug. Individuals homozygous for the T allele have four fold lower P-gp expression and higher digoxin plasma concentrations compared with CC individuals [93]. However, a later report showed the subjects with genotype TT had lower digoxin plasma concentrations in a much larger subject pool, a result opposite to the previous report [94]. Additional reports showed that there is no correlation between the genotype C3435T and pharmacokinetic profiles of P-gp substrates [95, 96]. There may not be a solid correlation between genotype C3435T and its phenotype because this may be linked with other functional polymorphism in the gene.

Additional functional variants of MDR1 have been disclosed. The functional relevance of nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 was reported. In vitro expression of MDR1 encoding Ala893 or a sitedirected Ser893 mutation indicated the enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the P-gp drug substrate fexofenadine. Subjects with homozygous Ala893 showed higher fexofenadine plasma exposure than those with homozygous Ser893 [97].

So far, at least 30 SNPs have been reported in the MDR1 gene. Human in vivo studies on MDR1 genotype-related pharmacokinetics have been reported. However, results were not always consistent. More work needs to be done to establish the correlation between the genotype and the phenotype. Haplotypes of these SNPs may allow a definition of this correlation.

Significance in Drug Development

Because P-gp functions as an efflux pump in cancer cell membranes which contributes resistance to many anticancer drugs leading to failure of chemotherapy. Although a few potent P-gp inhibitors are being developed, the efficacy has not been very satisfactory [98-100]. A challenge facing pharmaceutical scientists is to develop tumor-specific P-gp inhibitors to reverse the function of P-gp and to reach adequate accumulation of anticancer drugs in cancer cells [101]. The same challenge exists for targeted drug delivery where P-gp expression is abundant. One of the examples is the delivery of anti-epileptic drugs to the central nervous system [102]. P-gp in the BBB is the main obstacle to deliver drugs into the central nervous system. To develop a tissue-targeted P-gp inhibitor or delivery system would provide an additional strategy to treat many CNS diseases without increased exposure to peripheral tissues.

The determination of drug candidates as substrates, inhibitors, or inducers of cytochrome P450s has been a necessary step to meet the regulatory authorities' requirements. Lately, whether or not the drug candidate is a substrate, an inhibitor, or an inducer of P-gp has received a great attention to because of potential drug interaction issues. Many drugs are substrates of cytochrome P450 3A and P-gp, and their disposition is markedly affected by concurrent treatment with inducing agents, such as rifampin and St. John's wort. The inducing effects of both these agents have been reported to substantially decrease plasma concentrations and efficacy of substrate drugs including cyclosporine [103,104], protease inhibitors [105,106], oral contraceptives [107], and digoxin [108]. These drugs are substrates of cytochrome P4503A4 and/or substrates of P-gp. Both rifampin and St. John's wort are potent inducers of both CYPs and MDR1 through a common mechanism that is bound to the pregnane X receptor (PXR) [85]. The screening of PXR ligands has become a useful tool in drug development to select molecules with a lesser capacity to induce drug-metabolizing enzymes and MDR1 [109].


1. Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug Resistance in Cancer: Role of ATP-dependent Transporters. Nat. Rev. Cancer 2002, 2 (1), 48-58.

2. Schuetz, E.G.; Furuya, K.N.; Schuetz, J.D. Interindividual Variation in Expression of P-glycoprotein in Normal Human Liver and Secondary Hepatic Neoplasms. J. Pharmacol. Exp. Ther. 1995, 275 (2), 1011-1018.

3. Spahn-Langguth, H., et al. P-glycoprotein Transporters and the Gastrointestinal Tract: Evaluation of the Potential in vivo Relevance of in vitro Data Employing Talinolol as Model Compound. Int. J. Clin. Pharmacol. Ther. 1998, 36(1), 16-24.

4. Higgins, C.F. ABC Transporters: From Microorganisms to Man. Annu. Rev. Cell. Biol. 1992, 8, 67-113.

5. Hyde, S.C., et al. Structural Model of ATP-Binding Proteins Associated with Cystic Fibrosis, Multidrug Resistance and Bacterial Transport. Nature 1990, 346 (6282), 362-365.

6. Dean, M.; Rzhetsky, A.; Allikmets, R. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Genome Res. 2001, 11 (7), 1156-1166.

7. Allen, J.D., et al. The Mouse Bcrp 1/Mxr/Abcp Gene: Amplification and Overexpression in Cell Lines Selected for Resistance to Topotecan, Mitoxantrone, or Doxorubicin. Cancer Res. 1999, 59 (17), 4237-4241.

8. Juliano, R.L.; Ling, V. A Surface Glycoprotein Modulating Drug Permeability in Chinese Hamster Ovary Cell Mutants. Biochim. Biophys. Acta 1976, 455 (1), 152-162.

9. Riordan, J.R., et al. Amplification of P-glycoprotein Genes in Multidrug Resistant Mammalian Cell Lines. Nature 1985, 316 (6031), 817-819.

10. Smit, J.J., et al. Homozygous Disruption of the Murine mdr2 P-glycoprotein Gene Leads to a Complete Absence of Phospholipid from Bile and to Liver Disease. Cell 1993, 75 (3), 451-462.

11. van Helvoort, A., et al. MDR1 P-glycoprotein is a Lipid Translocase of Broad Specificity, While MDR3 P-glycoprotein Specifically Translocates Phosphatidylcholine. Cell 1996, 87 (3), 507-517.

12. Chen, C.J., et al. Genomic Organization of the Human Multidrug Resistance (MDR1) Gene and Origin of P-glycoproteins. J. Biol. Chem. 1990, 265 (1), 506-514.

13. van der Bliek, A.M., et al. Sequence of mdr3 cDNA Encoding a Human P-glycoprotein. Gene 1988, 71 (2), 401-411.

14. Schurr, E., et al. Characterization of the Multidrug Resistance Protein Expressed in Cell Clones Stably Transfected with the Mouse mdrl cDNA. Cancer Res. 1989, 49 (10), 2729-2733.

15. Borst, P.; Zelcer, N.; van Helvoort, A. ABC Transporters in Lipid Transport. Biochim. Biophys. Acta 2000, 1486 (1), 128-144.

16. Borst, P., et al. A Family of Drug Transporters: the Multidrug ResistanceAssociated Proteins. J. Natl. Cancer Inst. 2000, 92 (16), 1295-1302.

17. Pei, Q.L., et al. Increased Expression of Multidrug Resistance-Associated Protein 1 (mrpl) in Hepatocyte Basolateral Membrane and Renal Tubular Epithelia after Bile Duct Ligation in Rats. Hepatol. Res. 2002, 22 (1), 58-64.

18. Keppler, D.; Konig, J. Hepatic Canalicular Membrane 5: Expression and Localization of the Conjugate Export Pump Encoded by the MRP2 (cMRP/ cMOAT) Gene in Liver. Faseb, J. 1997, 11 (7), 509-516.

19. Keitel, V., et al. A Common Dubin-Johnson Syndrome Mutation Impairs Protein Maturation and Transport Activity of MRP2 (ABCC2). Am. J. Physiol. Gastrointest. Liver Physiol. 2003, 284 (1), G165-174.

20. Hirohashi, T., et al. Function and Expression of Multidrug Resistance Associated Protein Family in Human Colon Adenocarcinoma Cells (Caco-2). J. Pharmacol. Exp. Ther. 2000, 292 (1), 265-270.

21. Reid, G., et al. The Human Multidrug Resistance Protein MRP4 Functions as a Prostaglandin Efflux Transporter and is Inhibited by Nonsteroidal Antiinflammatory Drugs. Proc. Natl. Acad. Sci. USA, 2003.

22. Schuetz, J.D., et al. MRP4: A Previously Unidentified Factor in Resistance to Nucleoside-based Antiviral Drugs. Nat. Med. 1999, 5 (9), 1048-1051.

23. Sampath, J., et al. Role of MRP4 and MRP5 in Biology and Chemotherapy. AAPS Pharm. Sci. 2002, 4 (3), E14.

24. Madon, J., et al. Transport Function and Hepatocellular Localization of mrp6 in Rat Liver. Mol. Pharmacol. 2000, 57 (3), 634-641.

25. Belinsky, S.A., et al. Aberrant Promoter Methylation in Bronchial Epithelium and Sputum from Current and Former Smokers. Cancer Res. 2002, 62 (8), 2370-2377.

26. Germain, D.P., et al. Identification of Two Polymorphisms (c189G>C; c190T > C) in Exon 2 of the Human MRP6 Gene (ABCC6) by Screening of Pseudoxanthoma Elasticum Patients: Possible Sequence Correction? Hum. Mutat. 2000, 16 (5), 449.

27. Young, A.M.; Allen, C.E.; Audus, K.L. Efflux Transporters of the Human Placenta. Adv. Drug Deliv. Rev. 2003, 55 (1), 125-132.

28. Volk, E.L., et al. Overexpression of Wild-type Breast Cancer Resistance Protein Mediates Methotrexate Resistance. Cancer Res. 2002, 62 (17), 50355040.

29. Sargent, J.M., et al. Breast Cancer Resistance Protein Expression and Resistance to Daunorubicin in Blast Cells from Patients with Acute Myeloid Leukaemia. Br. J. Haematol. 2001, 115 (2), 257-262.

30. Hagenbuch, B.; Meier, P.J. The Superfamily of Organic Anion Transporting Polypeptides. Biochim. Biophys. Acta 2003, 1609 (1), 1-18.

31. Tirona, R.G.; Kim, R.B. Pharmacogenomics of Organic Anion-Transporting Polypeptides (OATP). Adv. Drug Deliv. Rev. 2002, 54 (10), 1343-1352.

32. Meier, P.J., et al. Substrate Specificity of Sinusoidal Bile Acid and Organic Anion Uptake Systems in Rat and Human Liver. Hepatology 1997, 26 (6), 1667-1677.

33. Kobayashi, D., et al. Involvement of Human Organic Anion Transporting Polypeptide OATP-B (SLC21A9) in pH-Dependent Transport across Intestinal Apical Membrane. J. Pharmacol. Exp. Ther. 2003.

34. Cui, Y., et al. Detection of the Human Organic Anion Transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in Liver and Hepatocellular Carcinoma. Lab. Invest. 2003, 83 (4), 527-538.

35. Russel, F.G.; Masereeuw, R.; van Aubel, R.A. Molecular Aspects of Renal Anionic Drug Transport. Annu. Rev. Physiol. 2002, 64, 563-594.

36. Sugiyama, Y.; Kusuhara, H.; Suzuki, H. Kinetic and Biochemical Analysis of Carrier-mediated Efflux of Drugs Through the Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Importance in the Drug Delivery to the Brain. J. Control Release 1999, 62 (1-2), 179-186.

37. Gao, B., et al. Localization of the Organic Anion Transporting Polypeptide 2 (Oatp2) in Capillary Endothelium and Choroid Plexus Epithelium of Rat Brain. J. Histochem. Cytochem. 1999, 47 (10), 1255-1264.

38. Angeletti, R.H., et al. The Choroid Plexus Epithelium is the Site of the Organic Anion Transport Protein in the Brain. Proc. Natl. Acad. Sci. USA 1997, 94 (1), 283-286.

39. Cha, S.H., et al. Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta. J. Biol. Chem. 2000, 275 (6), 4507-4512.

40. Eraly, S.A.; Nigam, S.K. Novel Human cDNAs Homologous to Drosophila Orct and Mammalian Carnitine Transporters. Biochem. Biophys. Res. Commun. 2002, 297 (5), 1159-1166.

41. Sun, W., et al. Isolation of a Family of Organic Anion Transporters from Human Liver and Kidney. Biochem. Biophys. Res. Commun. 2001, 283 (2), 417-422.

42. Saito, H.; Masuda, S.; Inui, K. Cloning and Functional Characterization of a Novel Rat Organic Anion Transporter Mediating Basolateral Uptake of Methotrexate in the Kidney. J. Biol. Chem. 1996, 277 (34), 20719-20725.

43. Pavlova, A., et al. Developmentally Regulated Expression of Organic Ion Transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am. J. Physiol. Renal. Physiol. 2000, 278 (4), F635-643.

44. Endou, H. Recent Advances in Molecular Mechanisms of Nephrotoxicity. Toxicol. Lett. 1998, 102-103, 29-33.

45. Takeda, M., et al. Interaction of Human Organic Anion Transporters with Various Cephalosporin Antibiotics. Eur. J. Pharmacol. 2002, 438 (3), 137142.

46. Kimura, H., et al. Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Transport of Prostaglandins. J. Pharmacol. Exp. Ther. 2002, 301 (1), 293-298.

47. Morita, N., et al. Functional Characterization of Rat Organic Anion Transporter 2 in LLC-PK1 Cells. J. Pharmacol. Exp. Ther. 2001, 298 (3), 11791184.

48. Takeuchi, A., et al. Multispecific Substrate Recognition of Kidney-specific Organic Anion Transporters OAT-K1 and OAT-K2. J. Pharmacol. Exp. Ther. 2001, 299 (1), 261-267.

49. Cha, S.H., et al. Identification and Characterization of Human Organic Anion Transporter 3 Expressing Predominantly in the Kidney. Mol. Pharmacol. 2001, 59 (5), 1277-1286.

50. Sweet, D.H., et al. Impaired Organic Anion Transport in Kidney and Choroid Plexus of Organic Anion Transporter 3 (Oat3 (Slc22a8)) Knockout Mice. J. Biol. Chem. 2002, 277 (30), 26934-26943.

51. Ugele, B., et al. Characterization and Identification of Steroid Sulfate Transporters of Human Placenta. Am. J. Physiol. Endocrinol. Metab. 2003, 284 (2), E390-398.

52. You, G. Structure, Function, and Regulation of Renal Organic Anion Transporters. Med. Res. Rev. 2002, 22 (6), 602-616.

53. Van Aubel, R.A.; Masereeuw, R.; Russel, F.G. Molecular Pharmacology of Renal Organic Anion Transporters. Am. J. Physiol. Renal. Physiol. 2000, 279 (2), F216-232.

54. Evans, W.E.; Christensen, M.L. Drug Interactions with Methotrexate. J. Rheumatol. 1985, 12 Suppl 12, 15-20.

55. Kekuda, R., et al. Cloning and Functional Characterization of a PotentialSensitive, Polyspecific Organic Cation Transporter (OCT3) most Abundantly Expressed in Placenta. J. Biol. Chem. 1998, 273 (26), 1597115979.

56. Motohashi, H., et al. Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney. J. Am. Soc. Nephrol. 2002, 13 (4), 866-874.

57. Sweet, D.H.; Miller, D.S.; Pritchard, J.B. Ventricular Choline Transport: a Role for Organic Cation Transporter 2 Expressed in Choroid Plexus. J. Biol. Chem. 2001, 276 (45), 41611-41619.

58. Murakami, H., et al. Characteristics of Choline Transport Across the Blood-Brain Barrier in Mice: Correlation with in vitro Data. Pharm. Res. 2000, 17 (12), 1526-1530.

59. Inui, K.I.; Masuda, S.; Saito, H. Cellular and Molecular Aspects of Drug Transport in the Kidney. Kidney Int. 2000, 58 (3), 944-958.

60. Koepsell, H. Organic Cation Transporters in Intestine, Kidney, Liver, and Brain. Annu. Rev. Physiol. 1998, 60, 243-266.

61. Stephens, R.H., et al. Region-dependent Modulation of Intestinal P-ermeability by Drug Efflux Transporters: in vitro Studies in mdrla (-/-) Mouse Intestine. J. Pharmacol. Exp. Ther. 2002, 303 (3), 1095-1101.

62. McKinnon, R.A.; McManus, M.E. Function and Localization of Cytochromes P450 Involved in the Metabolic Activation of Food-derived Heterocyclic Amines. Princess Takamatsu Symp. 1995, 23, 145-153.

63. Smith, A.J., et al. MDR3 P-glycoprotein, a Phosphatidylcholine Translocase, Transports Several Cytotoxic Drugs and Directly Interacts with Drugs as Judged by Interference with Nucleotide Trapping. J. Biol. Chem. 2000, 275 (31), 23530-23539.

64. Chishty, M., et al. Affinity for the P-glycoprotein Efflux Pump at the Blood-Brain Barrier May Explain the Lack of CNS Side-effects of Modern Antihistamines. J. Drug Target 2001, 9 (3), 223-228.

65. Rao, V.V., et al. 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. USA 1999, 96 (7), 3900-3905.

66. Asaba, H., et al. Blood-Brain Barrier is Involved in the Efflux Transport of a Neuroactive Steroid, Dehydroepiandrosterone Sulfate, via Organic Anion Transporting Polypeptide 2. J. Neurochem. 2000, 75 (5), 1907-1916.

67. Bart, J., et al. The Blood-Brain Barrier and Oncology: New Insights into Function and Modulation. Cancer Treat Rev. 2000, 26 (6) 449-462.

68. Cordon-Cardo, C. et al. Expression of the Multidrug Resistance Gene Product (P-glycoprotein) in Human Normal and Tumor Tissues. J. Histochem. Cytochem. 1990, 38 (9), 1277-1287.

69. MacFarland, A., et al. Stage-specific Distribution of P-glycoprotein in Firsttrimester and Full-term Human Placenta. Histochem. J. 1994, 26 (5), 417423.

70. Smit, J.W., et al. Absence or Pharmacological Blocking of Placental P-glycoprotein Profoundly Increases Fetal Drug Exposure. J. Clin. Invest. 1999 Nov, 104 (10), 1441-1447.

71. Leazer, T.M.; Klaassen, C.D. The Presence of Xenobiotic Transporters in Rat Placenta. Drug. Metab. Dispos. 2003, 31 (2), 153-167.

72. St-Pierre, M.V., et al. Characterization of an Organic Anion-Transporting Polypeptide (OATP-B) in Human Placenta. J. Clin. Endocrinol. Metab. 2002, 87(4), 1856-1863.

73. Sparreboom, A., et al. Limited Oral Bioavailability and Active Epithelial Excretion of Paclitaxel (Taxol) Caused by P-glycoprotein in the Intestine. Proc. Natl. Acad. Sci. USA 1997 Mar 4, 94 (5), 2031-2035.

74. van Asperen, J., et al. Enhanced Oral Bioavailability of Paclitaxel in Mice Treated with the P-glycoprotein Blocker SDZ PSC 833. Br. J. Cancer 1997, 76 (9), 1181-1183.

75. Greiner, B., et al. The Role of Intestinal P-glycoprotein in the Interaction of Digoxin and Rifampin. J. Clin. Invest. 1999 Jul, 104 (2), 147-153.

76. Schinkel, A.H., et al. Absence of the mdrla P-glycoprotein in Mice Affects Tissue Distribution and Pharmacokinetics of Dexamethasone, Digoxin, and Cyclosporin A.J. Clin. Invest. 1995 Oct, 96 (4), 1698-1705.

77. Kim, R.B., et al. The Drug Transporter P-glycoprotein Limits Oral Absorption and Brain Entry of HIV-1 Protease Inhibitors. J. Clin. Invest. 1998 Jan 15, 101 (2), 289-294.

78. Choo, E.F., et al. Pharmacological Inhibition of P-glycoprotein Transport Enhances the Distribution of HIV-1 Protease Inhibitors into Brain and Testes. Drug Metab. Dispos. 2000 Jun, 28 (6), 655-660.

79. Newman, M.I.; Dixon, R.; Toyonaga, B. OC144-093, a Novel P-glycoprotein Inhibitor for the Enhancement of Anti-epileptic Therapy. Novartis Found Symp. 2002, 243, 213-226; discussion 226-230, 231-235.

80. Lown, K.S., et al. Interpatient Heterogeneity in Expression of CYP3A4 and CYP3A5 in Small Bowel. Lack of Prediction by the Erythromycin Breath Test. Drug Metab. Dispos. 1994, 22 (6), 947-955.

81. Kolars, J.C., et al. CYP3A Gene Expression in Human Gut Epithelium. Pharmacogenetics 1994, 4 (5), 247-259.

82. Kivisto, K.T., et al. Expression of CYP3A4, CYP3A5 and CYP3A7 in Human Duodenal Tissue. Br. J. Clin. Pharmacol. 1996, 42 (3), 387-389.

83. McKinnon, R.A., et al. Characterisation of CYP3A Gene Subfamily Expression in Human Gastrointestinal Tissues. Gut 1995, 36 (2), 259267.

84. Benet, L.Z.; Cummins C.L. The Drug Efflux-Metabolism Alliance: Biochemical Aspects. Adv. Drug Deliv. Rev. 2001, 50 Suppl , S3-S11.

85. Geick, A.; Eichelbaum, M.; Burk, O. Nuclear Receptor Response Elements Mediate Induction of Intestinal MDR1 by Rifampin. J. Biol. Chem. 2001, 276 (18), 14581-14587.

86. Okamura, N., et al. Digoxin-Cyclosporin A Interaction: Modulation of the Multidrug Transporter P-glycoprotein in the Kidney. J. Pharmacol. Exp. Ther. 1993, 266 (3), 1614-1619.

87. Woodland, C.; Ito, S.; Koren, G. A Model for the Prediction of Digoxin-Drug Interactions at the Renal Tubular Cell Level. Ther. Drug Monit. 1998, 20 (2), 134-138.

88. Jalava, K.M.; Partanen, J.; Neuvonen, P.J. Itraconazole Decreases Renal Clearance of Digoxin. Ther. Drug. Monit. 1997, 19 (6), 609-613.

89. Hedman, A., et al. Interactions in the Renal and Biliary Elimination of Digoxin: Stereoselective Difference Between Guinine and Quinidine. Clin. Pharmacol. Ther. 1990, 47 (1), 20-26.

90. Hedman, A., et al. Digoxin-Verapamil Interaction: Reduction of Biliary but not Renal Digoxin Clearance in Humans. Clin. Pharmacol. Ther. 1991, 49 (3), 256262.

91. Yoshimoto, K., et al. A Polymorphic Hindill Site within the Human Multidrug Resistance Gene 1 (MDR1). Nucleic. Acids Res. 1988, 16(24), 11850.

92. Kioka, N., et al. P-glycoprotein gene (MDR1) cDNA from Human Adrenal: Normal P-glycoprotein Carries Gly185 with an Altered Pattern of Multidrug Resistance. Biochem. Biophys. Res. Commun. 1989, 162 (1), 224-231.

93. Hoffmeyer, S., et al. Functional Polymorphisms of the Human Multidrug-resistance Gene: Multiple Sequence Variations and Correlation of One Allele with P-glycoprotein Expression and Activity in vivo. Proc. Natl. Acad. Sci. U S A 2000, 97 (7), 3473-3478.

94. Sakaeda, T., et al. MDR1 Genotype-related Pharmacokinetics of Digoxin after Single Oral Administration in Healthy Japanese Subjects. Pharm. Res. 2001, 18 (10), 1400-1404.

95. Hitzl, M., et al. The C3435T Mutation in the Human MDR1 Gene is Associated with Altered Efflux of the P-glycoprotein Substrate Rhodamine 123 from CD56+ Natural Killer Cells. Pharmacogenetics 2001, 11 (4), 293298.

96. Gerloff, T., et al. MDR1 Genotypes do not Influence the Absorption of a Single Oral Dose of 1 mg Digoxin in Healthy White Males. Br. J. Clin. Pharmacol. 2002, 54 (6), 610-616.

97. Kim, R.B., et al. Identification of Functionally Variant MDR1 Alleles Among European Americans and African Americans. Clin. Pharmacol. Ther. 2001, 70 (2), 89-99.

98. Lehne, G., et al. The Cyclosporin PSC 833 Increases Survival and Delays Engraftment of Human Multidrug-resistant Leukemia Cells in Xenotrans-planted NOD-SCID Mice. Leukemia 2002, 76 (12), 2388-2394.

99. Rubin, E.H., et al. A Phase I Trial of a Potent P-glycoprotein Inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), Administered Orally in Combination with Doxorubicin in Patients with Advanced Malignancies. Clin. Cancer Res. 2002, 8 (12), 3710-3717.

100. Gruber, A., et al. A Phase I/II Study of the MDR Modulator Valspodar (PSC 833) Combined with Daunorubicin and Cytarabine in Patients with Relapsed and Primary Refractory Acute Myeloid Leukemia. Leuk. Res. 2003, 27 (4), 323-328.

101. Lehne, G. P-glycoprotein as a Drug Target in the Treatment of Multidrug Resistant Cancer. Curr. Drug Targets 2000, 7 (1), 85-99.

102. Newman, M.J.; Dixon, R.; Toyonaga, B. OC144-093, a Novel P-glycoprotein Inhibitor for the Enhancement of Anti-epileptic Therapy. Novartis Found Symp. 2002, 243, 213-226; discussion 226-230, 231-235.

103. Hebert, M.F., et al. Bioavailability of Cyclosporine with Concomitant Rifampin Administration is Markedly Less Than Predicted by Hepatic Enzyme Induction. Clin. Pharmacol. Ther. 1992, 52 (5), 453-457.

104. Mandelbaum, A., et al. Unexplained Decrease of Cyclosporin Trough Levels in a Compliant Renal Transplant Patient. Nephrol. Dial. Transplant. 2000, 15 (9), 1473-1474.

105. Barry, M., et al. Protease Inhibitors in Patients with HIV Disease. Clinically Important Pharmacokinetic Considerations. Clin. Pharmacokinet. 1997, 32 (3), 194-209.

106. Piscitelli, S.C., et al. Indinavir Concentrations and St John's Wort. Lancet 2000, 355 (9203), 547-548.

107. Dickinson, B.D., et al. Drug Interactions Between Oral Contraceptives and Antibiotics. Obstet. Gynecol. 2001, 98 (5 Pt 1), 853-860.

108. Johne, A., et al. Pharmacokinetic Interaction of Digoxin with an Herbal Extract from St John's Wort (Hypericum perforatum). Clin. Pharmacol. Ther. 1999, 66 (4), 338-345.

109. Ekins, S.; Erickson, J.A. A Pharmacophore for Human Pregnane X Receptor Ligands. Drug Metab. Dispos. 2002, 30 (1), 96-99.

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