Pharmaceutical Excipients Influence the Function of Human Uptake

Jul 18, 2012 - Before starting the experiments, the cells were washed once with incubation buffer (142 mM NaCl, 5 mM KCl, 1 mM K2HPO4, 1.2 mM MgSO4, 1...
0 downloads 12 Views 284KB Size
Download PDF
Article pubs.acs.org/molecularpharmaceutics

Pharmaceutical Excipients Influence the Function of Human Uptake Transporting Proteins Anett Engel, Stefan Oswald, Werner Siegmund, and Markus Keiser* Department of Clinical Pharmacology, Ernst-Moritz-Arndt-University Greifswald, 17487 Greifswald, Germany ABSTRACT: Although pharmaceutical excipients are supposed to be pharmacologically inactive, solubilizing agents like Cremophor EL have been shown to interact with cytochrome P450 (CYP)-dependent drug metabolism as well as efflux transporters such as P-glycoprotein (ABCB1) and multidrug resistance associated protein 2 (ABCC2). However, knowledge about their influence on the function of uptake transporters important in drug disposition is very limited. In this study we investigated the in vitro influence of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on the organic anion transporting polypeptides (OATP) 1A2, OATP2B1, OATP1B1, and OATP1B3 and the Na+/ taurocholate cotransporting polypeptide (NTCP). In stably transfected human embryonic kidney cells we analyzed the competition of the excipients with the uptake of bromosulfophthalein in OATP1B1, OATP1B3, OATP2B1, and NTCP, estrone-3-sulfate (E3S) in OATP1A2, OATP1B1, and OATP2B1, estradiol-17β-glucuronide in OATP1B3, and taurocholate (TA) in OATP1A2 and NTCP cells. SOL and CrEL were the most potent inhibitors of all transporters with the strongest effect on OATP1A2, OATP1B3, and OATP2B1 (IC50 < 0.01%). HPCD also strongly inhibited all transport proteins but only for substrates containing a sterane-backbone. Finally, PEG seems to be a selective and potent modulator of OATP1A2 with IC50 values of 0.05% (TA) and 0.14% (E3S). In conclusion, frequently used solubilizing agents were shown to interact substantially with intestinal and hepatic uptake transporters which should be considered in drug development. However, the clinical relevance of these findings needs to be evaluated in further in vivo studies. KEYWORDS: excipient, polyethylene glycol, hydroxypropyl-β-cyclodextrin, Solutol, Cremophor, uptake transporter, OATP, NTCP, HEK cells

■

INTRODUCTION Poor water solubility is a challenge for pharmaceutical technologists in the development of oral and parenteral dosage forms for many new molecular entities in clinical evaluation.1 One approach to get water insoluble drugs into a bioavailable pharmaceutical formulation is solubilizing them using excipients which should be without own pharmacological activity. However, several surfactants including Cremophor EL and polyethylene glycols have been shown to inhibit drug metabolizing cytochrome P450 (CYP) enzymes as well as efflux transporters such as P-glycoprotein (ABCB1) and multidrug resistance associated protein 2 (ABCC2) in vitro.2,3 Modulation of metabolism and efflux transport by excipients can influence the pharmacokinetics of many drugs in a clinically relevant manner as reported for the β-adrenoreceptor antagonist talinolol and D-α-tocopheryl polyethylene glycol 1000 succinate, the chemotherapeutic paclitaxel and Cremophor EL, or the cardiac glycoside digoxin and Cremophor RH40.4−6 Contrary to the flood of data on interactions of solubilizing agents with multidrug efflux transport proteins, there is nearly no evidence so far whether they also influence multidrug uptake transporter proteins such as members of the organic anion transporting polypeptide (OATP) family or the Na+/taurocholate cotransporting polypeptide (NTCP). However, increased recovery in liver perfusates, reduced uptake into tumor cells, and the nonlinear pharmacokinetics of paclitaxel in © 2012 American Chemical Society

the presence of Cremophor EL suggest an interaction of solubilizing agents with uptake transporters.7−9 During the last years, many researchers have shown that uptake carriers play a crucial role in drug disposition.10 In the intestine, OATP2B1 and OATP1A2 are expressed in the apical (luminal) membrane of enterocytes and thus are involved in the oral absorption of many drugs and endogenous compounds such as statins, quinolones, fexofenadine, bile salts, or hormones.11 Therefore, inhibition of uptake transporters in the gut may result in lowering systemic drug exposure and efficacy.12,13 In the liver, OATP1B1, OATP1B3, OATP2B1, and NTCP are located in the basolateral (sinusoidal) membrane of hepatocytes facilitating the cellular uptake of drugs from the sinusoidal blood, a basic precondition for subsequent metabolism and biliary excretion.11 Inhibition of multidrug uptake by OATPs is associated with lower presystemic hepatic elimination and leads to adverse drug effects as shown for the combination of statins with gemfibrozil or cyclosporine A.14 Furthermore, OATP1A2 and OATP2B1 are also expressed in the kidneys and at several blood−tissue Received: Revised: Accepted: Published: 2577

April 5, 2012 June 12, 2012 July 17, 2012 July 18, 2012 dx.doi.org/10.1021/mp3001815 | Mol. Pharmaceutics 2012, 9, 2577−2581

Molecular Pharmaceutics

Article

cellular viability was derived from the amount of reduced resazurin. Experiments were conducted in triplicates and repeated at least once. Critical Micelle Concentration. The critical micelle concentration (CMC) of the surfactants SOL and CrEL in incubation buffer was calculated via the surface tension of excipient dilutions in the range from 0.001% to 0.1% using a ring tensiometer K11 MK3 (Krü ss GmbH, Hamburg, Germany). Data Analysis. The transporter-mediated net uptake was obtained by subtracting the uptake into vector-transfected cells from the uptake into transporter-transfected cells. All data were normalized to the uptake in absence of any excipient. The half maximal inhibitory concentration (IC50) values were calculated by fitting the data to a sigmoidal dose−response regression curve using Prism 5.01 (GraphPad Software, San Diego, USA). The maximal inhibitory effect was calculated as the bottom of this curve or constrained to zero percent uptake if otherwise negative. All experiments were performed at least three times in triplicate.

barriers including the blood−brain barrier (BBB), where they affect renal clearance and tissue distribution of drugs.11 To confirm whether solubilizing agents might influence the activity of uptake carriers, we investigated the effects of polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol HS 15 (SOL), and Cremophor EL (CrEL) on the transport function of OATP1A2, OATP1B1, OATP1B3, OATP2B1, and NTCP in vitro.

■

MATERIAL AND METHODS Chemicals. PEG and HPCD were purchased from Applichem GmbH (Darmstadt, Germany). CrEL, estrone-3sulfate (E3S), estradiol-17β-glucuronide (E217βG), taurocholate (TA), and bromosulfophthalein (BSP) were obtained from Sigma-Aldrich (Taufkirchen, Germany). SOL was a generous gift from Bayer Healthcare (Berlin, Germany). [3H]-BSP (14 Ci/mmol) was purchased from Hartmann Analytic (Braunschweig, Germany), [3H]-TA (4.6 Ci/mmol), and [3H]-E217βG (41.8 Ci/mmol) from PerkinElmer Life and Analytical Sciences (Waltham, MA, USA) and [3H]-E3S (50 Ci/mmol) from Biotrend GmbH (Cologne, Germany). Competition Assays. Human embryonic kidney (HEK) cells stably transfected with OATP1A2, OATP1B1, OATP1B3, OATP2B1, or NTCP and the respective vector-transfected control cells were established as previously described.15,16 For competition assays, the cells were seeded in 24-well plates (BD Biosciences, Heidelberg, Germany) in full growth medium (minimal essential medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 2 mM nonessential amino acids; PAA Laboratories, Coelbe, Germany) at an initial density of 200.000 cells per well and cultivated for three days. Before starting the experiments, the cells were washed once with incubation buffer (142 mM NaCl, 5 mM KCl, 1 mM K2HPO4, 1.2 mM MgSO4, 1.5 mM CaCl2, 5 mM glucose, 12.5 mM HEPES; pH 7.3, 37 °C). [3H]-BSP, [3H]-E3S, [3H]E217βG, and [3H]-TA were dissolved in incubation buffer, and unlabeled BSP, E3S, E217βG, and TA were added to reach different final concentrations for each cell line (BSP 1 μM for OATP1B3, OATP2B1, NTCP, 0.05 μM for OATP1B1; E3S 1 μM for OATP1A2, OATP1B1, OATP2B1; E217βG 10 μM for OATP1B3; TA 10 μM for OATP1A2, NTCP). After incubation for 5 min at 37 °C in the absence or presence of up to 10% (w/v) of PEG, HPCD, SOL, or CrEL, the cells were washed three times with ice-cold incubation buffer and lysed with 0.5% Triton-X-100 and 0.5% sodium deoxycholate. Aliquots were mixed with 2 mL of scintillation cocktail (Rotiszint eco plus, Roth, Karlsruhe, Germany), and the intracellular accumulation of radioactivity was measured using a scintillation beta counter (type 1409; LKB-Wallac, Turku, Finland). The protein concentration was determined using the bicinchoninic acid assay according to the manufacturer’s instructions (Pierce, Rockford, IL, USA). The cellular influx of all substrates was in the linear range during the incubation time of 5 min. Cellular Viability. The cellular viability was verified using a resazurin assay kit (PrestBlue, Invitrogen, Karlsruhe, Germany). Each transfected cell line was incubated with the highest concentration of each excipient as used in the respective transport experiment. Pure medium, medium with dye, and cells with dye-containing medium in the absence of any excipient served as controls. Light absorption at 570 and 595 nm was measured at 0, 1, 2, and 4 h using a Tecan infinite M200 plate reader (Tecan GmbH, Crailsheim, Germany). The

■

RESULTS The excipients evaluated in our in vitro study were by no means inert regarding relevant interactions with the function of OATPs and NTCP. In detail, PEG selectively inhibited the uptake of E3S (IC50 = 0.14%) and TA (IC50 = 0.05%) by OATP1A2 (Figure 1), while the uptake of the probe substrates by OATP1B1, OATP1B3, OATP2B1, and NTCP was not influenced by PEG (data not shown).

Figure 1. Inhibition of the OATP1A2-mediated uptake of estrone-3sulfate (E3S) and taurocholate (TA) by polyethylene glycol 400; mean ± SD of three triplicates.

HPCD was a strong inhibitor of the E217βG uptake by OATP1B3 (IC50 = 0.001%). The uptake of E3S and TA by OATP1A2, OATP1B1, and OATP2B1 was inhibited with a lower potency (IC50 0.01% to 0.24%). The uptake of BSP by OATP1B1 and OATP2B1 was not influenced at concentrations of up to 1% (Table 1). Interestingly, with regard to the uptake of BSP by NTCP, HPCD exerted a stimulatory effect with a half-maximal effective concentration (EC50) of 0.5%, while the uptake of TA by NTCP was inhibited (Figure 2). SOL and CrEL were potent inhibitors of the uptake of BSP by OATP1B1, OATP1B3, OATP2B1, and NTCP (Figure 3). The uptake of estrogen conjugates by OATP1A2, OATP1B1, OATP1B3, and OATP2B1 and the uptake of TA by OATP1A2 were similarly inhibited (IC50 between 0.0003% and 0.3%, Table 2). Interestingly, SOL and CrEL were strong inhibitors of the BSP uptake by NTCP; however, the affinity to inhibit TA 2578

dx.doi.org/10.1021/mp3001815 | Mol. Pharmaceutics 2012, 9, 2577−2581

Molecular Pharmaceutics

Article

Table 1. Interaction of Hydroxypropyl-β-cyclodextrin with OATPs and NTCPa transporter

substrate

OATP1A2

E3S TA

OATP2B1

E3S

OATP1B1

BSP E3S

OATP1B3

BSP E217βG

NTCP

BSP TA BSP

IC50 (10−3% w/v) 27 (23, 31) 25 (19, 32) 10 (8.5, 12) no effect 240 (180, 300) no effect 1.0 (0.66, 1.6) no effect 4600 (3500, 6100) 520* (390, 690)

Table 2. Interaction of Solutol HS 15 and Cremophor EL with OATPs and NTCPa

MIE (%)

SOL

100 53

transporter

substrate

OATP1A2

E3S

87

TA

no effect 100

OATP2B1

E3S BSP

no effect 76

OATP1B1

no effect 100

E3S BSP

OATP1B3

E217βG

70* BSP

a

Geometric mean (geometric standard deviation) of IC50 (*EC50) values and the maximal inhibitory (*stimulatory) effect (MIE) from three triplicates are given. BSP, bromosulfophthalein; E3S, estrone-3sulfate; E217βG, estradiol-17β-glucuronide; TA, taurocholate.

NTCP

TA BSP

CrEL

IC50 (10−3% w/v)

MIE (%)

IC50 (10−3% w/v)

MIE (%)

7.4 (7.0, 7.9) 4.1 (2.9, 5.8) 11 (9.6, 12) 0.95 (0.78, 1.2) 21 (18, 24) 290 (260, 330) 1.9 (1.3, 2.9) 8.7 (6.3, 12) 1500 (1300, 1800) 5.8 (5.0, 6.8)

95

0.54 (0.47, 0.62) 0.34 (0.28, 0.42) 1.1 (0.81, 1.6) 9.8 (7.6, 13) 190 (170, 210) 300 (190, 490) 1.0 (0.86, 1.2) 4.7 (3.6, 6.1) 2800 (2400, 3300) 12 (8.2, 16)

100

97 91 87 83 94 82 100 100 67

78 88 100 100 96 66 76 100 78

a

Geometric mean (geometric standard deviation) of IC50 values and the maximal inhibitory effect (MIE) from three triplicates are given. BSP, bromosulfophthalein; E3S, estrone-3-sulfate; E217βG, estradiol17β-glucuronide; TA, taurocholate.

OATPs and NCTP. Because these excipients are frequently used in many oral or intravenous drug formulations and because OATPs and NCTP were shown to be major variables in the disposition of many drugs, substantial pharmacokinetic interactions are expected after concomitant clinical use. PEG seems to be a selective modulator of OATP1A2. As the cosolvent does neither form complexes nor micelles and the uptake of E3S and TA was only inhibited in cells transfected with OATP1A2 but not with the other OATP isoforms or NTCP, a specific mechanism is proposed for OATP1A2 inhibition by PEG. Based on the average circulating blood volume of an adult, approximately 5 mL of pure PEG are required for intravenous administration to reach systemic concentrations close to the determined IC50 assuming entirely intravascular distribution of PEG. However, considering the slow infusion rates of marketed products of less than 0.6 mL/ min and the short terminal half-life of PEG in blood plasma of less than 18 min,17 PEG-containing drug formulations for

Figure 2. Effect of hydroxypropyl-β-cyclodextrin on the uptake of taurocholate (TA) and bromosulfophthalein (BSP) by NTCP; mean ± SD of three triplicates.

uptake by NTCP was 250 times lower. The CMC of both surfactants was 0.005% in incubation buffer. The cell viability was at least 80% for all cell lines and excipients in the tested concentration range.

■

DISCUSSION We could clearly demonstrate that PEG, HPCD, SOL, and CrEL are able to significantly modulate the function of human

Figure 3. Inhibition of the uptake of bromosulfophthalein by Solutol HS 15 (left) and Cremophor EL (right); mean ± SD of three triplicates. 2579

dx.doi.org/10.1021/mp3001815 | Mol. Pharmaceutics 2012, 9, 2577−2581

Molecular Pharmaceutics

Article

solubilizing agents may reduce oral bioavailability of quinolones by inhibition of intestinal uptake by OATP1A2 similar to fruit juices, probably lowering the therapeutic effect of the antibiotic.29,30 Furthermore, excipients are suspected by our data to inhibit the hepatic uptake of statins by OATP1B1 and OATP1B3, thus reducing their lipid lowering activity and, as a consequence of lowering hepatobiliary clearance, increasing the risk for myopathy and fatal rhabdomyolysis as described for pravastatin and loss-of-function polymorphisms of OATP1B1.31 In conclusion, we demonstrated that frequently used solubilizing agents interact with hepatic and intestinal uptake transporters to different extents additionally to their known modulating effects on ABCB1-mediated efflux and CYP3A4dependent drug metabolism.2,19 However, the clinical relevance should be evaluated in future clinical studies.

intravenous administration (e.g., torasemide, diazepam, temsirolimus) might possibly not reach effective concentrations at the transporter site for instance at the BBB to modulate OATP1A2mediated drug uptake into the brain. The same applies to ABCB1 for which PEG was found to be also a potent inhibitor.2 In the intestine, on the other hand, the fluid volume is extremely variable and may be negligibly small in a fasted state.18 Therefore, concentrations of orally administered PEGcontaining drug formulations might exceed the estimated IC50 values and OATP1A2-mediated intestinal absorption of coadministered drug substrates could be impaired. Additionally, the selectivity of PEG for OATP1A2 might be an experimental tool in further research to evaluate the specificity of OATP1A2 compared to other OATPs in vitro and in vivo. Interaction of HPCD with OATPs and NCTP was substratedependent in our study. This finding may indicate that HPCD does not directly interact with the studied transporter proteins but might form stable complexes with substrates belonging to the group of steranes subsequently reducing the concentration of free E3S, E217βG, and TA available for cellular uptake. Furthermore, HPCD and other cyclodextrins are known to form stable complexes with cholesterol.19,20 Thus, one may speculate that complexation might result in several interactions with many steranes and other lipophilic compounds such as glucocorticoids, oral contraceptives, and cardiac glycosides. In line with this assumption, tissue distribution of flurbiprofen and oridonin was markedly affected by HPCD after intravenous and oral administration in rodents.21,22 An interesting finding in our study was that HPCD inhibited the uptake of TA by NTCP but increased the uptake of BSP. The enhancement might be caused by an allosteric stimulation as recently described for OATP1B1, OATP1B3, and OATP2B1 using ibuprofen and progesterone as probe drugs.23,24 Complex formation with BSP is not assumed to be of major influence in the assay as BSP lacks a sterane moiety in its chemical structure contrarily to the other substrates used in our in vitro studies. SOL and CrEL inhibited all investigated uptake transporters. Uptake inhibition by SOL and CrEL at concentrations above the CMC of 0.005% could be due to micellar trapping of the substrates similar to the complexion by HPCD. However, the inhibition of OATP1A2, OATP1B3, and OATP2B1 occurred already below the CMC. Therefore, a mixed mechanism is suggested for SOL and CrEL whereby micellar trapping is probably the major mechanism of interaction for the less sensitive OATP1B1 and NTCP. According to our in vitro data, less than 600 μL of pure surfactant might be sufficient to inhibit OATP1A2, OATP1B3, and OATP2B1 in the intestine, liver, and at blood−tissue barriers. Therefore, alterations in absorption and tissue distribution of OATP substrates might occur with marketed drug formulations as demonstrated for SOL and colchicine or CrEL and paclitaxel.25−27 Judging from our in vitro data and above-mentioned animal studies from the literature modulation of uptake carriers by solubilizing agents might be of clinical relevance. Oral and intravenous drug formulations containing these excipients are employed in the treatment of HIV infections (ritonavir, tipranavir), cancer (paclitaxel), cardiovascular diseases (glyceryl trinitrate), and fever (acetaminophen) and in immunosuppression (cyclosporine A, tacrolimus). They may be frequently combined with drugs against infections (quinolones, macrolides) and for the treatment of metabolic syndrome and cardiovascular diseases (statins, repaglinide, glibenclamide, βblockers) that are substrates for OATPs.11,28 In this context,

■

AUTHOR INFORMATION

Corresponding Author

*Ernst-Moritz-Arndt-University Greifswald, Department of Pharmacology, Felix-Hausdorff-Str. 3, D-17487 Greifswald, Germany. Phone: +49 (0)3834 86-5665. Fax: +49 (0)3834 86-5631. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the German Federal Ministry of Education and Research (Grants 03IP612, InnoProfile and 03WKCC6C, Wachstumskern Centifluidic Technologies). The authors thank Bayer Healthcare for providing free Solutol HS 15 and are very grateful to Marten Moeller for laboratorytechnical and to Danilo Wegner for biometrical support.

■

REFERENCES

(1) Stegemann, S.; Leveiller, F.; Franchi, D.; de Jong, H.; Linden, H. When poor solubility becomes an issue: from early stage to proof of concept. Eur. J. Pharm. Sci. 2007, 31, 249−261. (2) Buggins, T. R.; Dickinson, P. A.; Taylor, G. The effects of pharmaceutical excipients on drug disposition. Adv. Drug Delivery Rev. 2007, 59, 1482−1503. (3) Hanke, U.; May, K.; Rozehnal, V.; Nagel, S.; Siegmund, W.; Weitschies, W. Commonly used nonionic surfactants interact differently with the human efflux transporters ABCB1 (p-glycoprotein) and ABCC2 (MRP2). Eur. J. Pharm. Biopharm. 2010, 76, 260−268. (4) Bogman, K.; Zysset, Y.; Degen, L.; Hopfgartner, G.; Gutmann, H.; Alsenz, J.; Drewe, J. P-glycoprotein and surfactants: effect on intestinal talinolol absorption. Clin. Pharmacol. Ther. 2005, 77, 24−32. (5) ten Tije, A. J.; Verweij, J.; Loos, W. J.; Sparreboom, A. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin. Pharmacokinet. 2003, 42, 665−685. (6) Tayrouz, Y.; Ding, R.; Burhenne, J.; Riedel, K. D.; Weiss, J.; Hoppe-Tichy, T.; Haefeli, W. E.; Mikus, G. Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40. Clin. Pharmacol. Ther. 2003, 73, 397−405. (7) Ellis, A. G.; Webster, L. K. Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL. Cancer Chemother. Pharmacol. 1999, 43, 13−18. (8) Liebmann, J.; Cook, J. A.; Lipschultz, C.; Teague, D.; Fisher, J.; Mitchell, J. B. The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines. Cancer Chemother. Pharmacol. 1994, 33, 331−339. (9) Sparreboom, A.; van Tellingen, O.; Nooijen, W. J.; Beijnen, J. H. Nonlinear pharmacokinetics of paclitaxel in mice results from the

2580

dx.doi.org/10.1021/mp3001815 | Mol. Pharmaceutics 2012, 9, 2577−2581

Molecular Pharmaceutics

Article

pharmaceutical vehicle Cremophor EL. Cancer Res. 1996, 56, 2112− 2115. (10) Giacomini, K. M.; Huang, S. M.; Tweedie, D. J.; Benet, L. Z.; Brouwer, K. L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K. M.; Hoffmaster, K. A.; Ishikawa, T.; Keppler, D.; Kim, R. B.; Lee, C. A.; Niemi, M.; Polli, J. W.; Sugiyama, Y.; Swaan, P. W.; Ware, J. A.; Wright, S. H.; Yee, S. W.; Zamek-Gliszczynski, M. J.; Zhang, L. Membrane transporters in drug development. Nat. Rev. Drug Discovery 2010, 9, 215−236. (11) Hagenbuch, B.; Gui, C. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 2008, 38, 778−801. (12) Dresser, G. K.; Bailey, D. G.; Leake, B. F.; Schwarz, U. I.; Dawson, P. A.; Freeman, D. J.; Kim, R. B. Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin. Pharmacol. Ther. 2002, 71, 11− 20. (13) Schwarz, U. I.; Seemann, D.; Oertel, R.; Miehlke, S.; Kuhlisch, E.; Fromm, M. F.; Kim, R. B.; Bailey, D. G.; Kirch, W. Grapefruit juice ingestion significantly reduces talinolol bioavailability. Clin. Pharmacol. Ther. 2005, 77, 291−301. (14) Hedman, M.; Neuvonen, P. J.; Neuvonen, M.; Holmberg, C.; Antikainen, M. Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression. Clin. Pharmacol. Ther. 2004, 75, 101−109. (15) Leonhardt, M.; Keiser, M.; Oswald, S.; Kuhn, J.; Jia, J.; Grube, M.; Kroemer, H. K.; Siegmund, W.; Weitschies, W. Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab. Dispos. 2010, 38, 1024−1028. (16) Mandery, K.; Bujok, K.; Schmidt, I.; Keiser, M.; Siegmund, W.; Balk, B.; Konig, J.; Fromm, M. F.; Glaeser, H. Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem. Pharmacol. 2010, 80, 1746−1753. (17) Yamaoka, T.; Tabata, Y.; Ikada, Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J. Pharm. Sci. 1994, 83, 601−606. (18) Schiller, C.; Frohlich, C. P.; Giessmann, T.; Siegmund, W.; Monnikes, H.; Hosten, N.; Weitschies, W. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment. Pharmacol. Ther. 2005, 22, 971−979. (19) Cai, C.; Zhu, H.; Chen, J. Overexpression of caveolin-1 increases plasma membrane fluidity and reduces P-glycoprotein function in Hs578T/Dox. Biochem. Biophys. Res. Commun. 2004, 320, 868−874. (20) Frijlink, H. W.; Eissens, A. C.; Hefting, N. R.; Poelstra, K.; Lerk, C. F.; Meijer, D. K. The effect of parenterally administered cyclodextrins on cholesterol levels in the rat. Pharm. Res. 1991, 8, 9−16. (21) Frijlink, H. W.; Franssen, E. J.; Eissens, A. C.; Oosting, R.; Lerk, C. F.; Meijer, D. K. The effects of cyclodextrins on the disposition of intravenously injected drugs in the rat. Pharm. Res. 1991, 8, 380−384. (22) Yan, Z.; Xu, W.; Sun, J.; Liu, X.; Zhao, Y.; Sun, Y.; Zhang, T.; He, Z. Characterization and in vivo evaluation of an inclusion complex of oridonin and 2-hydroxypropyl-beta-cyclodextrin. Drug Dev. Ind. Pharm. 2008, 34, 632−641. (23) Grube, M.; Kock, K.; Karner, S.; Reuther, S.; Ritter, C. A.; Jedlitschky, G.; Kroemer, H. K. Modification of OATP2B1-mediated transport by steroid hormones. Mol. Pharmacol. 2006, 70, 1735−1741. (24) Kindla, J.; Muller, F.; Mieth, M.; Fromm, M. F.; Konig, J. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1- and OATP1B3-mediated drug transport. Drug Metab. Dispos. 2011, 39, 1047−1053. (25) Bittner, B.; Guenzi, A.; Fullhardt, P.; Zuercher, G.; Gonzalez, R. C.; Mountfield, R. J. Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid. Arzneimittelforschung. 2002, 52, 684−688.

(26) Bittner, B.; Gonzalez, R. C.; Walter, I.; Kapps, M.; Huwyler, J. Impact of Solutol HS 15 on the pharmacokinetic behaviour of colchicine upon intravenous administration to male Wistar rats. Biopharm. Drug Dispos. 2003, 24, 173−181. (27) Smith, N. F.; Acharya, M. R.; Desai, N.; Figg, W. D.; Sparreboom, A. Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel. Cancer Biol. Ther. 2005, 4, 815−818. (28) Bailey, D. G. Fruit juice inhibition of uptake transport: a new type of food-drug interaction. Br. J. Clin. Pharmacol. 2010, 70, 645− 655. (29) Neuhofel, A. L.; Wilton, J. H.; Victory, J. M.; Hejmanowsk, L. G.; Amsden, G. W. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J. Clin. Pharmacol. 2002, 42, 461−466. (30) Wallace, A. W.; Victory, J. M.; Amsden, G. W. Lack of bioequivalence when levofloxacin and calcium-fortified orange juice are coadministered to healthy volunteers. J. Clin. Pharmacol. 2003, 43, 539−544. (31) Niemi, M.; Neuvonen, P. J.; Hofmann, U.; Backman, J. T.; Schwab, M.; Lutjohann, D.; von Bergmann, K.; Eichelbaum, M.; Kivisto, K. T. Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17. Pharmacogenet. Genomics 2005, 15, 303−309.

2581

dx.doi.org/10.1021/mp3001815 | Mol. Pharmaceutics 2012, 9, 2577−2581