Pharmacokinetics and toxicokinetics of d-serine in rats.

In the mammalian brain, d-serine acts as a co-agonist at the glycine-binding site on the N-methyl-d-aspartate receptor. Because plasma d-serine levels are significantly lower in patients with schizophrenia than in healthy subjects, d-serine has been proposed as a potential therapeutic agent for schizophrenia treatment. However, d-serine has a nephrotoxic effect in rats at high doses. The purpose of this study was to investigate the relationship between the plasma kinetics of d-serine and nephrotoxicity in rats. We administered d-serine intravenously (iv), orally (po), or intraperitoneally (ip) to male Wistar rats, and performed gas chromatography-mass spectrometry to measure the plasma concentrations of d- and l-serine. After iv administration (0.1 mmol/kg body weight (bw)), plasma d-serine declined multiexponentially with an elimination t1/2 of 108 ± 16 min, and the total clearance was 7.9 ± 0.9 ml/min/kg bw. The oral bioavailability of d-serine was estimated to be 94 ± 27%. To evaluate the dose-response relationship of d-serine-induced kidney injury and the plasma kinetics of d-serine, we injected d-serine into rats ip in doses ranging from 0.6 to 4.8 mmol/kg bw. Twenty-four hours after d-serine administration, histological changes indicating renal damage were observed in the kidneys of rats who received d-serine at doses of 1.8-4.8 mmol/kg bw; the severity of the tubular injury increased with increasing d-serine dose. When the Cmax value of d-serine was approximately >2 µmol/ml, the plasma creatinine increased remarkably 24 h after d-serine administration. This suggests that the Cmax of d-serine could be a good predictor of d-serine-induced nephrotoxicity.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

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.

Simultaneous determination of serine enantiomers in plasma using Mosher's reagent and stable isotope dilution gas chromatography-mass spectrometry.

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.

Development of patient-friendly preparations: preparation of a new allopurinol mouthwash containing polyethylene(oxide) and carrageenan.

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.