Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

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Stomatitis is a harmful side effect induced by high and/or multiple dosing of cytotoxic drugs such as 5-fluorouracil. Allopurinol mouthwash has been used to prevent stomatitis induced by cancer chemotherapy. In the present study, the pharmaceutical utility of allopurinol mouthwash (Alkox-mw), which consists of polyethylene(oxide) (Alkox) and iota-carrageenan (INA), was investigated as a possible material for a new oral dosage preparation for improving the adhesiveness onto the oral mucosa. From the observation of the gel formation, which was studied as a function of the variety of the added Alkox and/or INA, the preferential compositions of Alkox-mw (Alkox:INA % ratio) seemed to be 1.0:(0-1.0) and (0-3.0):0.4, respectively. The adhesiveness and the spinnability of various allopurinol mouthwashes were also investigated using a creep meter. The adhesiveness of Alkox-mw increased with the increase in the amount of added Alkox. Furthermore, the adhesion force of Alkox-mw was greater than that of allopurinol mouthwash consisting of sodium carboxymethylcellulose (CMC-Na). From the in vitro assessment of mimicking the effusion of the allopurinol mouthwashes from the surface of the oral mucosa, the effusion of Alkox-mws was retarded by the added Alkox. The results obtained in the present study suggest that Alkox-mws may be useful as a new dosage form that adheres to the oral mucosa.

D-Serine is a co-agonist of the N-methyl-D-aspartate receptor in glutamate neurotransmission and has been proposed as a potential therapeutic agent for schizophrenia. However, D-serine also acts as a nephrotoxic substance in rats at high doses. To investigate the pharmacokinetics and toxicokinetics of D-serine, a method for the stereoselective determination of serine enantiomers in rat plasma was developed using GC-MS with selected ion monitoring (GC-MS-SIM). DL-[(2)H(3)]Serine was used as an internal standard to account for losses associated with the extraction, derivatization and chromatography. Serine enantiomers were purified by cation-exchange chromatography using BondElut SCX cartridge and derivatized with HCl in methanol to form methyl ester followed by subsequent N,O-diacylation with optically active (+)-α-methoxy-α-trifluoromethylphenylacetyl chloride to form epimeric amide. Quantitation was performed by SIM of the molecular-related ions of the epimers in the chemical ionization mode. The intra- and inter-day reproducibility of the assay was less than 5% for D-serine and 3% for L-serine. The method was successively applied to study the pharmacokinetics of D-serine in rats.

ObjectiveThe present study aimed to clarify the pulmonary disposition of a cyclosporine derivative, IMM 125 (IMM), inhaled as a dry powder consisting of micronized particles for the treatment of asthma. The physiological mechanism of pulmonary accumulation of IMM, as well as the relative exposure of such an immunosuppresive drug between systemic and local (target) sites, were particularly investigated in order to assess the advantages of the inhalation route in comparison with a systemic one. MethodIn vitro study: Alveolar macrophages (mp) were collected by Bronchoalveolar Lavage (BAL) from golden hamsters, washed and incubated with microparticles to measure in vitro uptake. In vivo study: The microparticles were inhaled to male rats by nose only exposure for 15 min. At various time post dose, animals were sacrificed and the lung lumenal content by BAL as well as various organs were collected. Drug concentrations in BAL fluid (supernatant and pellet by centrifugation, i.e., dissolved+crystal and mp), blood afid various organs were measured by HPLC. The same design of experiment was performed after an intratracheal (i.t.) administration of the drug solution. PBPK modeling: Presystemic drug disposition was modeled as shown in the scheme below, where fractions of inhalation dose are either deposited in the lung lumen or swallowed into the digestive organs. The microparticles in the lung are considered either to be incorporated to tissue, to exist in the lumen, or to be associated with mp. Both pulmonary and intestinal absorptions are considered. The systemic drug disposition is fixed with a formerly developed PBPK model'). Results and Discussion The suspended IMM particles were progressively incorporated into the mp in vitro. An ultrastructural microscopic observation using a stereological method suggested phagocytosis as the uptake mechanism.') This mp loaded IMM was stable; mp/medium ratio was 70% after 6 days of incubation. The uptake dynamics is not far different from the inert insoluble reference (latex) but a dose-dependent tendency was observed for IMM ( Fig. 1), due presumably to the difference in structural (crystalline vs. spherical) or physicochemical properties (hydrophilicity, etc.).In vivo study in rats consisted of inhalation (powder) and i.t. (solution) administrations; the latter was for evaluating and modeling the PK process of drugs which were dissolved from the lumenal microparticles. Elimination of Lt. dose from the lung was fairly rapid, suggesting a rapid pulmonary absorption or mucus transfer, while that after inhalation was substantially slow. The result indicates that dissolution or mp retention of microparticles is the rate determining process of the lung clearance after inhalation. Indeed, a progressive microparticle uptake into mp was similarly observed in vivo as in the in vitro system (Fig.2). All the in vivo data were integrated and analyzed