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.

Mirabegron (MBR) is a ß3-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 F24h and AUC0-24h values of MBR in MBR-EFA, MBR-NDA, and MBR-PG rats were increased by 143-195% compared with the MBR rats. The absolute F24h, relative F24h, and AUC0-24h 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.

Effect of Water Extract of Mangosteen Pericarp on Donepezil Pharmacokinetics in Mice.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb-drug combinations have been increasingly attempted to alleviate Alzheimer's disease (AD), the PK evaluation of herb-drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs. Recently, the memory-enhancing effects of water extract of mangosteen pericarp (WMP) has been reported, suggesting a potential for the combination of WMP and donepezil (DNP) for AD treatment. Thus, it was evaluated how WMP affects the PK change of donepezil, including systemic exposure and tissue distribution in mice after simultaneous oral administration of DNP with WMP. Firstly, co-treatment of WMP and donepezil showed a stronger inhibitory effect (by 23.0%) on the neurotoxicity induced by Aß(25-35) in SH-SY5Y neuroblastoma cells than donepezil alone, suggesting that the combination of WMP and donepezil may be more effective in moderating neurotoxicity than donepezil alone. In PK interaction, WMP increased donepezil concentration in the brain at 4 h (by 63.6%) after administration without affecting systemic exposure of donepezil. Taken together, our results suggest that WMP might be used in combination with DNP as a therapy for AD.

A New Therapeutic Approach Using a Calcilytic (AXT914) for Postsurgical Hypoparathyroidism in Female Rats.

Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.