Satoshi Kobayashi

Renal clearance of a recombinant granulocyte colony-stimulating factor, nartograstim, in rats.

AbstractPurpose. To clarify the role of the kidney in the elimination of a recombinant human granulocyte colony-stimulating factor, nartograstim, we have investigated its pharmacokinetics in rats with renal failure. Methods. The steady-state clearance (CLss) were determined by the intravenous infusion for 4 hr to unilateral renally-ligated and cisplatin-treated rats, whose renal functions were about 50 and 10 % of controls, respectively. Results. CLss of nartograstim (27 ml/hr/kg) in the renally-ligated rats at a high infusion rate was significantly lower (25%) than in control rats (p<0.05). CLss in these rats, at a low infusion rate was 95 ml/hr/kg, 14 % lower than in control rats. The saturable CLss in these rats, 68 ml/hr/kg, was not significantly different from control rats (75 ml/hr/kg, p>0.05). Also, CLss in cisplatin-treated rats with extensive renal failure, at a high infusion rate, decreased to 57 % of controls. Furthermore, the total body clearances (CLtot) of nartograstim after bolus intravenous administration to renally-ligated and cisplatin-treated rats were reduced to 33–49 % of controls. Conclusions. These results suggest that the kidney may be responsible for 40– 50 % of the nonsaturable clearance of nartograstim. Thus, the kidney should make a major contribution to the elimination of nartograstim when rats are given a high dose of nartograstim, which saturates the receptor-mediated clearance.

Determination of benidipine hydrochloride in human plasma by capillary column gas chromatography—negative ion chemical ionization mass spectrometry

A highly sensitive and specific determination method of a new calcium antagonist, benidipine hydrochloride, in human plasma has been developed using capillary column gas chromatography with negative ion chemical ionization mass spectrometry. A deuterated analogue of benidipine hydrochloride was used as an internal standard. Benidipine hydrochloride was extracted from plasma with diethyl ether under basic conditions, back-extracted with 0.5 M sulphuric acid, and reextracted with diethyl ether under basic conditions. For gas chromatography, a solventless injection port was used, and the whole extract was injected. Fragment ions at m/z 488 (benidipine) and m/z 493 (internal standard) were used as monitoring ions for selected-ion monitoring. The detection limit was 0.02 ng/ml with 0.5 ml of plasma. The coefficient of variation of intra-day assay was 17.4% and 12.1% at the 0.02 and 0.1 ng/ml levels, respectively. This method has made it possible to detect the plasma level of unchanged drug up to 12 h after an 8-mg oral dose of benidipine hydrochloride to humans.

Disposition of Marograstim (KW-2228). (2). Plasma level, distribution, metabolism and excretion of 125I-KW-2228 following multiple subcutaneous administrations of KW-2228 to rats.

Plasma concentration, distribution, metabolism and excretion of KW-2228 following multiple subcutaneous administrations for 10 days were studied in rats using 125I-labelled KW-2228 in rats, and the obtained results were compared with those after single administration. 50μg/kg/day of KW-2228 were given to rats for 9 days and 125I-KW-2228 on the 10th day only, and then concentration of radioactivity was determined. Cmax, AUC, T1/2 and Cltot calculated from TCA-insoluble radioactivity after multiple administrations did not differ from those obtained following single administration. The highest concentration of radioactivity was found in the kidney, same as observed by single administration. The distribution and elimination in other tissues, including the target organ, bone marrow, were also similar to those after single administration, indicating no cumulative effect, Most of radioactive substances were, like after single administration, excreted in urine, which were TCA-soluble and a low molecular weight metabolites such as 125I. These results show that none of plasma pharmacokinetics, distribution, metabolism and excretion differ from those obtained after single administration and that the pharmacokinetics of KW-2228 is not affected by multiple subcutaneous administration.