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Biomedical subjects

O Nagata

Publications and source records attributed to O Nagata.

77 records · Page 5Linked to original sources
PubMedDate not supplied

Physiological pharmacokinetics of a new muscle-relaxant, inaperisone, combined with its pharmacological effect on blood flow rate.

This study was designed to develop a physiologically-based pharmacokinetic/pharmacodynamic model for drugs whose pharmacokinetics are influenced by their dose-dependent pharmacological effects. Since blood flow rate is one of the important factors that determine the distribution and elimination processes of drugs, we used inaperisone [IPS, (+/-)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)-propiophenone hydrochloride], a novel centrally acting muscle relaxant that has been found by us to significantly alter muscle and fat blood flow rates in a dose-dependent manner, as a model compound. With regard to the changes in muscle blood flow rate exhibited by IPS, the brain was shown to be the major site of action based on changes in the observed blood flow rates, determined by the 51Cr-labeled microsphere method, in rats injected iv and intracerebroventricularly with various doses of IPS. Consequently, the blood flow rates in the muscle and fat were well correlated with the concentration of IPS in the brain using Hill's equation. Moreover, hepatic and renal intrinsic clearances of IPS at steady-state were determined by the constant iv infusion method. The saturation of in vivo hepatic and renal metabolisms of IPS was found at venous plasma concentrations higher than 1 microgram/ml. Taken all together, we developed a physiologically-based pharmacokinetic model of IPS combined with its pharmacological effect in rats, which could simulate the concentration-dependent changes in blood flow rates based on the drug concentrations at the site of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Structure-tissue distribution relationship based on physiological pharmacokinetics for NY-198, a new antimicrobial agent, and the related pyridonecarboxylic acids.

Comparative physiological pharmacokinetic analysis has been carried out to elucidate the different tissue distribution characteristics among eight pyridonecarboxylic acids including newly developed NY-198. The urinary and fecal recoveries of NY-198 were 76.3 +/- 1.3% and 21.0 +/- 0.1% of the dose (mean +/- SE, N = 3), respectively, after the iv administration of [14C]NY-198 as a 20 mg/kg dose. Model-independent moment analysis of the serum concentration-time profile of [14C]NY-198 gave the volume of distribution at steady state per body weight (Vdss/BW) as 1150 ml/kg. Intrinsic renal clearance (CLint.kd) and intrinsic hepatic clearance (CLint.lv) were estimated to be 7.68 ml/min/kg and 6.33 ml/min/kg, respectively, by the cumulative urinary recovery and the area under the curve of the serum concentration-time profile of NY-198 and the blood flow rate. The tissue-to-serum partition coefficients (Kp) were determined from the analysis of the tissue and serum concentration-time profiles after iv bolus or infusion of nalidixic acid, NY-198, and its structural analogue NY-239. These values were also determined from the analysis of similar data reported in the literature for the other pyridonecarboxylic acids (enoxacin, miloxacin, ofloxacin, pefloxacin, and pipemidic acid). The Kp values of NY-198 ranged from 0.22 to 4.85 and were very similar to those for ofloxacin, being the highest in the disposing organs, kidneys and liver, the lowest in fat and brain, and modest in the other nondisposing organs. A good correlation (r = 0.981) was obtained between serum unbound fraction (fp) and the steady state distribution volume per body weight (Vd(ss)/BW), which was determined from the tissue partition coefficient. Additionally, comparatively good correlations were also obtained between fp and the Kp or apparent tissue-to-serum concentration ratio (Kp,app). Thus, the difference of serum unbound fraction has been demonstrated for the determining factor of the structure-dependent tissue distribution difference, whereas the tissue binding has been suggested to be only slightly different for respective tissues among PCA derivatives. The concentration-time profile for serum and tissues (lung, heart, muscle, kidney, liver, spleen, gut, bone, skin, and brain) was predicted for NY-198 by physiological pharmacokinetics using the averaged tissue-to-serum unbound concentration ratio (Kp,f) which was determined from the Kp,f of eight PCA analogues.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Inter-individual differences of 4-[4-(4-methylphenyl)-phenylmethoxy-1-piperidinyl]butyric acid disposition in rats: possible involvement of genetic polymorphism.

Inter-individual differences of drug plasma concentration were recognized in outbred rats after an oral or intravenous administration of (+)-4-[4-(4-methylphenyl)phenylmethoxy-1-piperidinyl]butyric acid hydrochloride ((+)-MPPB). Rats could be divided into two phenotypes, the rapid metabolizing (RM) group and the slow metabolizing (SM) group. The hepatic clearance of RM-phenotyped Sprague-Dawley rats was about 10 times larger than that of the SM group. Outbred male and female Sprague-Dawley rats and male Wistar rats were mixtures of the RM and SM groups. On the other hand, all inbred male Lewis rats were RM, and all inbred male F344 and ACI rats were SM. This study was undertaken to investigate the inter-individual differences of (-)-MPPB and the metabolic pathways of (+)- and (-)-MPPB. When (-)-MPPB was orally administered to male Sprague-Dawley rats, similar inter-individual differences of plasma concentration were recognized. RM-phenotyped Sprague-Dawley rat liver microsomes metabolized (+)-MPPB to 4-hydroxymethylphenyl-MPPB (M1), and (-)-MPPB to M1 and 4'-hydroxyphenyl-MPPB (M2). The formation of these metabolites was less with SM-phenotyped than with RM-phenotyped Sprague-Dawley rat liver microsomes. The kinetic parameters of M1 formation from (+)-MPPB by RM-phenotyped rat liver microsomes were characteristic of a two-enzyme system with a 100-fold difference in their affinities (KM values). On the other hand, SM-phenotyped rats have only the low-affinity enzyme system. An inhibition study demonstrated that both enzymes were cytochrome P450.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗