Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice

Abstract

Mirabegron (MBR) is a β₃-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (F), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability. Nevertheless, the pharmacokinetic feasibility of these co-amorphous dispersions has not been evaluated. Therefore, this study aimed to characterize the pharmacokinetic profiles of MBR-EFA, MBR-NDA, and MBR-PG in rats and mice. Our results exhibited that relative F_24h and AUC_0-24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143-195% compared with the MBR rats. The absolute F_24h, relative F_24h, and AUC_0-24h values of MBR in MBR-EFA and MBR-NDA mice were enhanced by 178-234% compared with the MBR mice. In tissue distribution, MBR was extensively distributed in the gastrointestinal tract, liver, kidneys, lung, and heart of mice. Notably, MBR distribution in the liver, kidneys, and lung was considerably high in MBR-EFA, MBR-NDA, or MBR-PG mice compared with MBR mice. These findings highlight the potential of these co-amorphous dispersions to enhance oral F of MBR.

Keywords: bioavailability; co-amorphous dispersion; mirabegron; pharmacokinetics; tissue distribution.

Figure 1

(a) Chemical structures of MBR, MBR-EFA, MBR-NDA, and MBR-PG. (b) Absorption process after oral administration of MBR and its co-amorphous dispersions.

Figure 2

Mean (±S.D.) plasma concentrations of MBR after oral administration of MBR (□; n = 14), MBR-EFA (■; n = 10), MBR-NDA (■; n = 11), and MBR-PG (■; n = 10) at a dose of 30 mg/kg as MBR to rats. The “n” represents the number of rats used in each group.

Figure 3

(a) Mean (±S.D.) plasma concentrations of MBR after intravenous administration of MBR (□; n = 13) at a dose of 5 mg/kg as MBR to mice. (b) Mean (± S.D.) plasma concentrations of MBR after oral administration of MBR (□; n = 16), MBR-EFA (■; n = 15), MBR-NDA (■; n = 13), and MBR-PG (■; n = 15) at a dose of 50 mg/kg as MBR to mice. The “n” represents the number of mice used in each group.

Figure 4

Mean (±S.D.) (a) concentrations (µg/mL in plasma and µg/g tissue) and (b) tissue/plasma ratios of MBR (▩; n = 15 for intravenous and □; n = 15 for oral administration), MBR-EFA (■; n = 15), MBR-NDA (■; n = 15), and MBR-PG (■; n = 15) in various tissues at 0.5, 2, 4, 8, and 10 h after intravenous administration of MBR (5 mg/kg as MBR) and oral administration (50 mg/kg as MBR) of MBR, MBR-EFA, MBR-NDA, and MBR-PG to mice. * MBR-NDA and MBR-PG mice were significantly different (p < 0.05) from MBR mice. ** MBR-EFA and MBR-PG mice were significantly different (p < 0.05) from MBR mice. + MBR-NDA mice were significantly different (p < 0.05) from MBR mice. The “n” represents the number of mice used in each group.

Figure 4

Mean (±S.D.) (a) concentrations (µg/mL in plasma and µg/g tissue) and (b) tissue/plasma ratios of MBR (▩; n = 15 for intravenous and □; n = 15 for oral administration), MBR-EFA (■; n = 15), MBR-NDA (■; n = 15), and MBR-PG (■; n = 15) in various tissues at 0.5, 2, 4, 8, and 10 h after intravenous administration of MBR (5 mg/kg as MBR) and oral administration (50 mg/kg as MBR) of MBR, MBR-EFA, MBR-NDA, and MBR-PG to mice. * MBR-NDA and MBR-PG mice were significantly different (p < 0.05) from MBR mice. ** MBR-EFA and MBR-PG mice were significantly different (p < 0.05) from MBR mice. + MBR-NDA mice were significantly different (p < 0.05) from MBR mice. The “n” represents the number of mice used in each group.