Intestinal Absorption Mechanism of Mirabegron, a Potent and

Apr 5, 2013 - Drug Metabolism Research Laboratories, Astellas Pharma Inc., Osaka, Japan. ‡ ADME & Tox. Research Institute, Sekisui Medical Co., Ltd...
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Intestinal Absorption Mechanism of Mirabegron, a Potent and Selective β3‑Adrenoceptor Agonist: Involvement of Human Efflux and/or Influx Transport Systems Shin Takusagawa,*,† Fumihiko Ushigome,† Hiroyuki Nemoto,‡ Yutaka Takahashi,§ Qun Li,∥ Virginie Kerbusch,⊥ Aiji Miyashita,† Takafumi Iwatsubo,† and Takashi Usui† †

Drug Metabolism Research Laboratories, Astellas Pharma Inc., Osaka, Japan ADME & Tox. Research Institute, Sekisui Medical Co., Ltd., Ibaraki, Japan § Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., Shizuoka, Japan ∥ Pharmacology Research Laboratories-Translational and Development Pharmacology-Europe, Astellas Pharma Europe B.V., Leiden, The Netherlands ⊥ PharmAspire Consulting, Wijchen, The Netherlands ‡

S Supporting Information *

ABSTRACT: Mirabegron, a weak-basic compound, is a potent and selective β3-adrenoceptor agonist for the treatment of overactive bladder. Mirabegron extended release formulation shows dose-dependent oral bioavailability in humans, which is likely attributable to saturation of intestinal efflux abilities leading to higher absorption with higher doses. This study evaluated the membrane permeability of mirabegron and investigated the involvement of human intestinal transport proteins in the membrane permeation of mirabegron. Transcellular transport and cellular/vesicular uptake assays were performed using Caco-2 cells and/or human intestinal efflux (P-glycoprotein [P-gp], breast cancer resistance protein [BCRP], and multidrug resistance associated protein 2 [MRP2]) and influx (peptide transporter 1 [PEPT1], OATP1A2, and OATP2B1) transporter-expressing cells, vesicles, or Xenopus laevis oocytes. The absorptive permeability coefficients of mirabegron in Caco-2 cells (1.68−1.83 × 10−6 cm/s) at the apical and basal pH of 6.5 and 7.4, respectively, were slightly higher than those of nadolol (0.97−1.41 × 10−6 cm/s), a low permeability reference standard, but lower than those of metoprolol and propranolol (both ranged from 8.49 to 11.6 × 10−6 cm/ s), low/high permeability boundary reference standards. Increasing buffer pH at the apical side from 5.5 to 8.0 gradually increased the absorptive permeation of mirabegron from 0.226 to 1.66 × 10−6 cm/s, but was still less than the value in the opposite direction (11.0−14.2 × 10−6 cm/s). The time- and concentration-dependent transport of mirabegron was observed in P-gp-expressing cells and OATP1A2-expressing oocytes with apparent Km values of 294 and 8.59 μM, respectively. In contrast, no clear BCRP-, MRP2-, PEPT1-, or OATP2B1-mediated uptake of mirabegron was observed in their expressing vesicles or cells. These findings suggest that mirabegron has low-to-moderate membrane permeability and P-gp is likely to be involved in its efflux into the lumen in the intestinal absorption process. The results also suggest that mirabegron could possibly be transported by intestinal influx transporters as well as simple diffusion. KEYWORDS: mirabegron, intestinal absorption, double peak pharmacokinetic profile, dose-dependent oral bioavailability, membrane permeability, Caco-2, transporter, P-glycoprotein, OATP1A2

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INTRODUCTION Mirabegron, 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, a potent and selective human β3-adrenoceptor agonist,1 is a new drug approved for the treatment of overactive bladder (OAB) in Japan, Europe, and the US. It is the first in a new class of drugs with a different mode of action compared with antimuscarinic medications, the current standard of care for the treatment of patients with OAB.2 Mirabegron once-daily for 12 weeks © 2013 American Chemical Society

demonstrated superior efficacy compared with placebo in the treatment of symptoms of OAB.3,4 In a human mass balance study where [14C]mirabegron was orally administered as a solution at a 160 mg dose, all individual Received: Revised: Accepted: Published: 1783

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Louis, MO, US). [ 3 H]Digoxin, [3 H]E 2 17βG, [ 3 H]E3S ammonium salt, and [14C]mannitol were obtained from PerkinElmer (Waltham, MA, US). [3H]Methotrexate and [3H]glycylsarcosine were synthesized at American Radiolabeled Chemicals, Inc. (St. Louis, MO, US), and Moravek Biochemicals (St. Louis, MO, US), respectively. Methotrexate was purchased from Nacalai Tesque, Inc. (Kyoto, Japan), naringin from Wako Pure Chemical Industries (Osaka, Japan), and Ko143 from Tocris Bioscience (Ellisville, MO, US). All other reagents were of either high-performance liquid chromatography (HPLC) grade or analytical grade, and were obtained from commercial sources. Test System. Cells. Caco-2 cells (human epithelial colonic adenocarcinoma cells) were obtained from American Type Culture Collection (Manassas, VA, US). LLC-PK1-MDR1 cells (porcine kidney epithelial cells transfected with human MDR1/ P-gp cDNA) and the control cells (LLC-PK1-mock cells) were used under the sublicense from Becton, Dickinson and Company (Franklin Lakes, NJ, US). The HEK293 cells (American Type Culture Collection), a transfected cell line derived from human embryonic kidney, that stably express peptide transporter 1 (PEPT1) or organic anion transporting polypeptide 2B1 (OATP2B1, also known as OATP-B) (HEK293-PEPT1 or -OATP2B1 cells) as well as the control cells (HEK293-mock cells) were constructed using pcDNA 3.1 (+) (Life Technologies, Carlsbad, CA, US) at Sekisui Medical Co., Ltd. (Ibaraki, Japan). The cell culture conditions were as described previously with minor modifications of culture medium.12−15 Briefly, Caco-2 cells and LLC-PK1-MDR1 or -mock cells were seeded at a density of 1 × 105 and 1.3 × 105 cells/cm2, respectively, in culture insert of trans-cellular transport devices (HTS Multiwell insert system, polyethylene terephthalate porous filter; pore size, 1 μm; area, 0.3 cm2; or culture insert, polyethylene terephthalate porous filter; pore size, 3 μm; area, 0.3 cm2; BD Falcon, Becton, Dickinson and Company). The cells were incubated in a CO2 incubator (37 °C, CO2: 5%) for 21 or 22 days for Caco-2 cells or for 7 to 9 days for LLC-PK1-MDR1 or -mock cells to prepare cell monolayers for determination of the permeability coefficient. HEK293-PEPT1, -OATP2B1, or -mock cells were seeded in collagen I-coated 24-well plates (BD Falcon, Becton, Dickinson and Company) at a density of approximately 2.4 × 105 cells/ well and incubated in a CO2 incubator for 2 days. The transepithelial electric resistance (TEER) was measured using the EVOM epithelial voltohmmeter (World Precision Instruments, Sarasota, FL, US) or the Millicell-ERS (electrical resistance system) (Millipore, Billerica, MA, US) for confirming the Caco-2 or LLC-PK1 cell monolayers formation before the permeability or bidirectional transport experiments. Cell monolayers having TEER values less than 100 Ω·cm2 were not included in the study. Vesicles. The human breast cancer resistance protein (BCRP, also known as ABCG2)- and multidrug resistance associated protein 2 (MRP2, also known as ABCC2)expressing vesicles (Sf9 membrane fraction derived from the baculovirus-infected insect) manufactured by GenoMembrane, Inc. (Kanagawa, Japan) were used. Xenopus laevis Oocytes. The full-length cDNA of OATP1A2 (also known as OATP-A) was cloned from the cDNA library (SuperScript cDNA Library Human Liver [female, 9 years] 10422-012) and subcloned into pcDNA3.2 at Sekisui Medical Co., Ltd. After linearization of the plasmid with PmeI, the capped cRNA of OATP1A2 was synthesized by

concentration−time profiles of mirabegron in plasma showed distinct double peaks at approximately 0.5 to 1 h and 2 to 4 h after administration.5 Mirabegron is formulated as an extended release tablet, using the oral controlled absorption system (OCAS) technology. OCAS is a hydrophilic gel-forming matrix tablet invented by Astellas Pharma Inc., of which the gel rapidly and completely hydrates in the upper gastrointestinal (GI) tract and this ensures continuous and consistent drug release throughout the entire length of the GI tract.6 The OCAS formulation showed an average peak plasma concentration of mirabegron at approximately 4 h after oral administration.7,8 A double-peak profile was only occasionally observed (unpublished observation). Enterohepatic recycling is unlikely to be associated with mirabegron absorption, as there were no fluctuations after intravenous administration.7 Oral mirabegron OCAS exhibited a greater-than-doseproportional increase in exposure.7,8 Mirabegron is metabolized to at least 10 metabolites by multiple enzymes (butyrylcholinesterase, UDP-glucuronosyltransferases, CYP3A4, CYP2D6, etc.), with no single predominating clearance pathway.5,9 The contribution of CYP3A4, which is regioselectively expressed in the gut, is considered to be limited. Mirabegron metabolites also demonstrated a more-than-dose-proportional increase in Cmax and AUC,8 similar to parent, indicating that the greaterthan-dose-proportional increase in mirabegron exposure is not caused by saturable first-pass metabolism. A postulated mechanism for the supraproportionality is saturation of transporter-mediated efflux as the dose of mirabegron increases and concentrations in the gut lumen increase. Ogihara et al.10 reported that a series of efflux transporter Pglycoprotein (P-gp, also known as multidrug-resistance protein 1 [MDR1] and ABCB1) substrates with low absorptive permeability coefficient of 55% of dose5). The pH-dependent permeability of mirabegron was additionally investigated because “lipophilic” (octanol−water log P-

mirabegron shows low membrane permeability, it is most likely to be classified as a class 3 drug. In this study, we evaluated the membrane permeability of mirabegron and investigated the involvement of human intestinal transport proteins in the membrane permeation of mirabegron, trying to elucidate the intestinal absorption mechanism of mirabegron. First, the membrane permeability of mirabegron was evaluated by a transcellular transport assay using human intestinal epithelial Caco-2 cell monolayers as outlined in the FDA’s BCS Guidance for Industry.29 We chose Caco-2 cell monolayers because they remain intact at apical pH values of 5.5 to 8 that cover almost the entire physiologic range of the intestinal tract.30−32 The use of Caco-2 cell monolayers has been widely adopted for evaluation of intestinal drug absorption and was demonstrated to have a good correlation between drug permeability and the oral absorption of the same 1790

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expressed in the luminal membrane of the small intestine and were indicated as being of importance with respect to drug disposition and/or toxicity in the human intestinal epithelia.41 P-gp has been clearly implicated in causing poor and dosedependent oral absorption of several basic β-blockers such as pafenolol,42 celiprolol,43 and talinolol.44 Mirabegron OCAS formulation also shows dose-dependent oral bioavailability in humans,7,8 which is likely attributable to saturation of intestinal efflux abilities leading to higher absorption with higher doses. In this study, mirabegron was demonstrated to be a substrate of P-gp but not of BCRP and MRP2. The affinity of mirabegron to P-gp (apparent Km = 294 μM) was relatively low, and comparable to that of celiprolol (apparent Km = 1000 μM).43 The passive permeation of mirabegron without involvement of P-gp, which is the Papp value in the presence of 30 μM quinidine in Caco-2 cells at both apical and basal pH of 7.4, was around 7 (Figure 3B) and slightly higher than that of pafenolol and talinolol, the permeability of which is low-to-moderate,45 suggesting that mirabegron possesses low-to-moderate passive permeability when excluding the P-gp effect. The protein expression levels of P-gp between intestinal segments are highly variable between individuals, and no region-dependent expression is established in humans.46 However, it is reported that the protein level and the activity of P-gp were the highest in the middle ileum in rats.47 Functional activity of P-gp between intestinal segments in humans has not been elucidated yet. It may be hypothesized that the high solution dose saturates all P-gp efflux in the upper part, leading to a high first peak, and that, in contrast, the release from OCAS formulation in the upper part is too slow to saturate P-gp, leading to significant efflux and a much lower or even absent first peak. Last, the involvement of human intestinal influx transporters was investigated by an uptake study using transporterexpressing cells or Xenopus laevis oocytes. We selected the candidate influx transporters that are responsible for intestinal absorption of mirabegron based on its chemical structure. Many β-blockers including celiprolol, acebutolol, atenolol, nadolol, sotalol, labetalol, and talinolol are reported to be substrates of OATP1A2 and/or OATP2B1.48,49 Mirabegron possesses a peptide bond in its chemical structure, and several peptide-like drugs such as β-lactam antibiotics cephalexin, anticancer agent bestatin, etc. exhibit high oral absorption due to the contribution of an influx transporter PEPT1.50,51 OATP1A2 and OATP2B1 localize at the brush-border membrane of intestinal epithelial cells as well as PEPT1.50,52,53 We therefore focused on these three influx transporters and investigated their ability to transport mirabegron. No significant transport of mirabegron was observed by OATP2B1 and PEPT1, while a significant transport activity was observed by OATP1A2. Interestingly, OATP1A2 exhibited different pH-dependent transport activities between the substrates, mirabegron and E3S. While a higher transport activity was observed at pH 7.4 for mirabegron, E3S exhibited higher activity at a weak-acidic pH of 6.0 (Table 2). As mentioned earlier, mirabegron was hypothesized to be absorbed by influx transporters from the upper small intestine, where the luminal pH is weak-acidic. Since OATP1A2 showed higher transport activity at pH 7.4 than at pH 6.0, OATP1A2 was not considered as the influx transporter involved in the absorption of mirabegron from the upper small intestine. Also, mirabegron exposure increases more than dose-proportionally after oral dosing of OCAS formulation, suggesting higher capacity of the influx transport/diffusion than that of the efflux

Figure 7. Concentration-dependent OATP1A2-mediated uptake of [14C]mirabegron into Xenopus laevis oocytes. pH was set at 7.4. The apparent Km and Vmax values were calculated from the relationship between the OATP1A2-mediated uptake clearance and the concentration of mirabegron by the least-squares method according to the equation shown in Data Analyses.

Table 2. pH-Dependent Uptake of [14C]Mirabegron and [3H]E3S into Control and OATP1A2-Expressing Xenopus laevis Oocytesa cleared vol (μL/oocyte) compound

concn (μM)

[14C]mirabegron

3

[3H]E3S

0.05

pH

control

6.0 7.4 6.0 7.4

NDb 0.0879c 0.0447 ± 0.0087 0.0280 ± 0.0056

OATP1A2 1.43 2.92 5.09 2.44

± ± ± ±

0.45 0.51 0.43 0.25

a 3

[ H]E3S was used as a typical substrate of OATP1A2. Each value represents the mean ± SD of six to seven oocyte determinations. bNot detected. cValue of one oocyte.

value from 1.75 to 3.65) but not “hydrophilic” (log P-value from −0.79 to 0.76) basic β-blockers have been reported to show pH-dependent passive permeability in the perfused rat intestine in situ. 38 The physicochemical properties of mirabegron are similar to those of lipophilic basic β-blockers, with a log P-value of 2.2 (calculated from its pKa values and a log D7.4 value of 1.5). In this study, increasing buffer pH at the apical side from 5.5 to 8.0 resulted in a decrease in the Papp ratio of mirabegron as reported for other basic drugs.30,39 A remarkable decrease in the Papp ratio of mirabegron was observed between the apical pH of 6.5 and 7.4, suggesting a marked increase in the absorptive permeability between these apical pH values. The pH value in the human proximal small intestine, jejunum, is 6.6 ± 0.5 (mean ± SD, n = 55), while that in the distal small intestine, ileum, is 7.5 ± 0.5 (mean ± SD, n = 58).40 Therefore, it was considered that site-dependent passive diffusion in the intestine might contribute to the second peak of mirabegron after oral administration as a solution. However, the absorptive permeability at the apical pH of 8.0 was still less than the value in the opposite direction, suggesting that mirabegron is incompletely absorbed even at the lower part of the small intestine and that the effects of transporters could not be denied. Second, the involvement of human intestinal efflux transporters was investigated using Caco-2 cells and/or transporterexpressing cells or vesicles. We selected P-gp, BCRP, and MRP2 as the candidate efflux transporters because they are 1791

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(3) Khullar, V.; Amarenco, G.; Angulo, J. C.; Cambronero, J.; Hoye, K.; Milsom, I.; Radziszewski, P.; Rechberger, T.; Boerrigter, P.; Drogendijk, T.; Wooning, M.; Chapple, C. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: Results from a randomised European-Australian phase 3 trial. Eur. Urol. 2013, 63, 283−95. (4) Nitti, V.; Auerbach, S.; Martin, N.; Calhoun, A.; Lee, M.; Herschorn, S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J. Urol. 2013, 189, 1388−95. (5) Takusagawa, S.; van Lier, J. J.; Suzuki, K.; Nagata, M.; Meijer, J.; Krauwinkel, W.; Schaddelee, M.; Sekiguchi, M.; Miyashita, A.; Iwatsubo, T.; van Gelderen, M.; Usui, T. Absorption, metabolism and excretion of [(14)C]mirabegron (YM178), a potent and selective beta(3)-adrenoceptor agonist, after oral administration to healthy male volunteers. Drug Metab. Dispos. 2012, 40, 815−24. (6) Michel, M. C.; Korstanje, C.; Krauwinkel, W. M, K. The pharmacokinetic profile of tamsulosin oral controlled absorption system (OCAS(R)). Eur. Urol. 2005, No. Suppl. 4, 15−24. (7) Eltink, C.; Lee, J.; Schaddelee, M.; Zhang, W.; Kerbusch, V.; Meijer, J.; van Marle, S.; Grunenberg, N.; Kowalski, D.; Drogendijk, T.; Moy, S.; Iitsuka, H.; van Gelderen, M.; Matsushima, H.; Sawamoto, T. Single dose pharmacokinetics and absolute bioavailability of mirabegron, a beta3-adrenoceptor agonist for treatment of overactive bladder. Int. J. Clin. Pharmacol. Ther. 2012, 50, 838−49. (8) Krauwinkel, W.; van Dijk, J.; Schaddelee, M.; Eltink, C.; Meijer, J.; Strabach, G.; van Marle, S.; Kerbusch, V.; van Gelderen, M. Pharmacokinetic properties of mirabegron, a beta3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin. Ther. 2012, 34, 2144−60. (9) Takusagawa, S.; Yajima, K.; Miyashita, A.; Uehara, S.; Iwatsubo, T.; Usui, T. Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron, a potent and selective β3-adrenoceptor agonist. Xenobiotica 2012, 42, 957−967. (10) Ogihara, T.; Kamiya, M.; Ozawa, M.; Fujita, T.; Yamamoto, A.; Yamashita, S.; Ohnishi, S.; Isomura, Y. What kinds of substrates show P-glycoprotein-dependent intestinal absorption? Comparison of verapamil with vinblastine. Drug Metab. Pharmacokinet. 2006, 21, 238−44. (11) Cao, X.; Yu, L. X.; Barbaciru, C.; Landowski, C. P.; Shin, H. C.; Gibbs, S.; Miller, H. A.; Amidon, G. L.; Sun, D. Permeability dominates in vivo intestinal absorption of P-gp substrate with high solubility and high permeability. Mol. Pharmaceutics 2005, 2, 329−40. (12) Adachi, Y.; Suzuki, H.; Sugiyama, Y. Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm. Res. 2001, 18, 1660−8. (13) Ishiguro, N.; Maeda, K.; Kishimoto, W.; Saito, A.; Harada, A.; Ebner, T.; Roth, W.; Igarashi, T.; Sugiyama, Y. Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab. Dispos. 2006, 34, 1109−15. (14) Noé, J.; Portmann, R.; Brun, M. E.; Funk, C. Substratedependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab. Dispos. 2007, 35, 1308−14. (15) Umehara, K.; Iwai, M.; Adachi, Y.; Iwatsubo, T.; Usui, T.; Kamimura, H. Hepatic uptake and excretion of (-)-N-{2-[(R)-3-(6,7dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidi no]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, in rats and humans. Drug Metab. Dispos. 2008, 36, 1030−8. (16) Ito, K.; Kato, Y.; Tsuji, H.; Nguyen, H. T.; Kubo, Y.; Tsuji, A. Involvement of organic anion transport system in transdermal absorption of flurbiprofen. J. Controlled Release 2007, 124, 60−8. (17) Hidalgo, I. J.; Raub, T. J.; Borchardt, R. T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 1989, 96, 736−49.

transport. OATP1A2 had higher affinity for mirabegron (apparent Km = 8.59 μM) than P-gp, indicating that the capacity of OATP1A2 becomes saturated before the saturation of efflux transporter P-gp. Therefore, it was considered that OATP1A2 is not a major contributor for the intestinal absorption of mirabegron when administered as the OCAS formulation, which is in line with the finding that the mRNA expression level of OATP1A2 is very low in the small intestine.54 However, the findings that mirabegron has lowto-moderate membrane permeability and is a substrate of OATP1A2 suggest that not only OATP1A2 but also some intestinal influx transporters such as other OATP might participate in the absorption of mirabegron. It is reported that the mRNA of OATP3A1, OATP4A1, OATP5A1, etc. is expressed in the small intestine.54 In conclusion, we have shown that mirabegron has low-tomoderate membrane permeability and P-gp is likely to be involved in its efflux into the lumen in the intestinal absorption process. The results also suggest that mirabegron could possibly be transported by intestinal influx transporters as well as simple diffusion. This is the first report showing that the efflux transporter P-gp and the influx transporter OATP1A2 are capable of transporting mirabegron.

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ASSOCIATED CONTENT

S Supporting Information *

Concentration-dependent transcellular transport of [14C]mirabegron across monolayers of LLC-PK1-mock (control) and -MDR1 (P-gp-expressing) cells. Concentration-dependent uptake of [14C]mirabegron into control and OATP1A2expressing Xenopus laevis oocytes. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Drug Metabolism Research Laboratories, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. Tel: (+81) 6-6210-6969. Fax: (+81) 6-6390-1090. E-mail: shin. [email protected]. Notes

The authors declare the following competing financial interest(s): S.T., F.U., Y.T., A.M., T.I., T.U. are employees of Astellas Pharma Inc., Japan. Q.L. is an employee of Astellas Pharma Europe B.V., The Netherlands. H.N. is an employee of Sekisui Medical Co. Ltd., Japan. V.K. is paid to be a Consultant to Astellas.

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ACKNOWLEDGMENTS The authors would like to thank Yuuji Awamura (Astellas Pharma Inc.), who was responsible for the analysis of physicochemical properties of mirabegron.

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