This study assessed the specificity of displacement potencies of MCI-9042 ((±)-1-[o-[2-(m-methoxyphenyl)ethyl]phenoxy]-3-(dimethylamino)-2-propyl hydrogen succinate hydrochloride), a new antiplatelet agent, in [³H]4-bromo-2, 5-dimethoxyphenylisopropylamine ([³H]DOB) and [³H] ketanserin binding to 5HT₂-serotonergic receptors in the rat brain using the radioligand binding method. The assessment of the displacement potencies of MCI-9042 and its derivative, M-1 (((±)-1-[2-(3-methoxyphenyl) ethyl] phenoxy]-3-(dimethylamino)-2-propanol)hydrochloride), on α₁-, α₂-, β-adrenergic, 5HT₁-, 5HT₂- and muscarinic receptors were also studied. MCI-9042 and M-1 showed strong displacement effects to 5HT₂-receptors using [³H] DOB binding and [³H] ketanserin binding sites, and weak displacement effects for [³H] serotonin, [³H] prazosin, [³H] p-aminoclonidine, [³H] CGP12177 and [³H] QNB binding to 5HT₁-, α₁-, α₂-, β-adrenergic receptors and muscarinic receptors. Thus, the present study suggests that MCI-9042 is specific for 5HT₂-receptor.

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The present study examined changes in [³H] prazosin, [¹²⁵I] iodocyanopindolol and [³H] nitrendipine binding to α₁-and β₁-adrenergic receptors and Ca²⁺ binding sites of cardiac muscle isolated from fetal Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), using the radioligand binding assay method. The catecholamine concentration in the cardiac muscle of both groups was also determined. The B_max values in β₁-adrenoceptors and Ca²⁺ binding sites in SHR cardiac muscle were lower than those of WKY, but values for SHR α₁-adrenoceptors were higher than those of WKY. The K_d values of β₁-adrenoceptors in cardiac muscles of SHRs were also lower than those of WKY. On the other hand, there were no differences between the catecholamine concentrations in fetal SHR and WKY cardiac muscles. Thus, significant differences in both α₁-and β₁-adrenoceptors and Ca²⁺ binding sites were already present in fetal SHR hearts, thus suggesting that the changes in fetal hearts of SHRs may be caused by genetic defects in the mother rats at early age.

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Species difference in glucuronidation of morphine was studied using mice, rats, guinea pigs and rabbits in vivo and in vitro. Morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) were determined by high-performance liquid chromatography. M-3-G was the major urinary metabolite of morphine in all these animal species. However, a remarkable species difference was observed in the urinary excretion of the M-6-G. Excretion ratios of the M-3-G to M-6-G were approximately 4 : 1 and 50 : 1 in guinea pigs and rabbits, respectively. The urinary excretion of M-6-G in mice and rats was too small to be determined. On the other hand, the ratios of uridine diphosphateglucuronyltransferase (UDPGT) activities toward 3-and 6-hydroxyl groups of morphine in liver microsomes of mice, rats, guinea pigs and rabbits were approximately 300 : 1, 90 : 1, 4 : 1 and 40 : 1, respectively. Ratios of two morphine UDPGT activities in the liver microsomes of guinea pigs and rabbits, thus, reflected those of urinary excretion of morphine glucuronides.

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In the isolated vas deferens of the guinea pig, the inhibitory effects of manganese (Mn²⁺) on the contractions induced by potassium (K⁺) were decreased when the contractions were induced repeatedly in the presence of Mn²⁺. This phenomenon appeared to be tachyphylaxis to the inhibitory effects of Mn²⁺. After the repetitive application of K⁺ with Mn²⁺, the phasic component of K⁺-induced contraction was restored, while the tonic component of this contraction and resting tone were augmented by the deprivation of extracellular Mn²⁺. When Mn²⁺ was applied during the tonic component of the K⁺ -induced contraction, the phasic component of the next contraction induced by K⁺ in the absence of Mn²⁺ was slightly inhibited and the tonic component of the contraction was potentiated. When extracellular calcium concentration was increased, the inhibitory effect of Mn²⁺ on K⁺-induced contractions was reduced, while the tachyphylaxis to Mn²⁺ also appeared. Under this condition, the resting tone was markedly increased when the K⁺-induced contraction was repeated in the presence of Mn²⁺. In the calcium-free medium containing Mn²⁺, although K⁺ caused slow and monophasic contractions, the magnitude of the contractions was much smaller than that of the contractions induced in the normal medium containing Mn²⁺. These results suggest that the tachyphylaxis was not produced by the decrement of the inhibitory effects of Mn²⁺ on the contractions but by the augmenting effects of intracellularly accumulated Mn²⁺ and that these augmenting effects of Mn²⁺ are not due to the direct action on the contractile proteins but due to the indirect action of Mn²⁺ which increased the availability of Ca²⁺.

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The effect of the traditional Chinese herbal medicines (Tin Chuan Tang and Hsiao Ching Long Tang) on the serum concentrations and pharmacokinetics of aminophylline was examined in three different ages of SD rats. Each traditional Chinese herbal medicine was orally preadministered to SD rats for one week and then aminophylline was administered intravenously. The serum concentrations and pharmacokinetic parameters of theophylline were estimated by a two-compartment open model. The liver isolated after the last blood sampling was homogenized and the activity of hepatic cytochrome p-450 was determined. Significant difference was found in some pharmacokinetic parameters of theophylline such as K₁₀, t_1/2, Cl and V_d for three different ages of SD rats without pretreatment with Chinese herbal drugs (p<0.05). However, pretreatment with Tin Chuan Tang or Hsiao Ching Long Tang did not affect the pharmacokinetic parameters of theophylline in three different ages of SD rats (p<0.05). We also found that there was no correlation between age and activity of cytochrome p-450 of SD rats (p>0.05). The decline in some pharmacokinetic parameters of the-ophylline in the elderly rats perhaps might be attributed to the decrease in hepatic blood flow and liver volume. It is concluded that there was no drug interaction between theophylline and Tin Chuan Tang or Hsiao Ching Long Tang in the different ages of SD rats.

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A method is presented to estimate log P values using molecular surface area, electrostatic potentials and charge transfer interactions derived from three-dimensional molecular structures. Estimated log P values for 63 small organic molecules with a variety of structures gave a correlation coefficient of 0.983 with a standard deviation of 0.260. The method is applicable to rather complex and large molecules. A striking feature of the method is that it can estimate the log P values of novel compounds to which "fragment constant approaches"have not been applicable so far.

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Sclerogen is a mitogenic protein isolated from the buffer extracts (3S) from sclerotia and shows significant mitogenic activity after heat denaturation accompanied with conformational changes. Experiments have been carried out to assess the distribution of sclerogen in several extracts from sclerotia and mycelia of this fungus by using the anti-serum against sclerogen. The anti-serum against the native- and heat denatured-sclerogen (anti-sclerogen-M and -MB serum, respectively) were prepared from Japanese white rabbits. These anti-sera showed different cross-reactivity to sclerogen-M and -MB from the results of immunoblotting after normal-polyacrylamide gel electrophoresis (normal-PAGE), suggesting that sclerogen-MB became to have different epitope(s) after heat denaturation of sclerogen-M. The result of immunoblotting after sodium dodecyl sulfate (SDS)-PAGE suggested that these anti-sera also recognized the random coil site(s) where the conformational specificity was not concerned, and that sclerogen (like substance(s)) existed not only in mild extracts (e.g. phosphate buffer) but also in fractions extracted from mycelia of S. sclerotiorum IFO 9395. Taken together with the results of the mitogenic activity of the representative extracts from sclerotia, at least two kinds of the mitogenic substances would exist in sclerotia ; one would be extracted by mild conditions, and the other would be difficult to extract and require drastic conditions such as hot water extraction.

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The pharmacokinetics of pirarubicin and its active metabolite, doxorubicin, were studied after intravenous administration of pirarubicin (25-45 mg/m²) to ten pediatric patients. The concentration-time curves of pirarubicin in both blood and plasma showed representative biphasic patterns. Pirarubicin concentrations decreased rapidly from 0.5 to 2 h after administration and then decreased slowly until 24 h in all subjects. High concentrations of the metabolite, doxorubicin, were detected at 0.5 h after administration of pirarubicin which decreased gradually until 24 h. The area under the concentration-time curve from 0 to 24h (AUC_0-24) of pirarubicin and doxorubicin in blood were 3-4 times higher than those in plasma, suggesting that these drugs had a high affinity for blood cells. The AUC_0-24 ratio of doxorubicin to pirarubicin in plasma was calculated to be 0.441. It might be indicated that not only pirarubicin but also doxorubicin are responsible for the therapeutic efficacy and the incidence of toxicity of pirarubicin. The pharmacokinetics of pirarubicin in pediatric patients was fundamentally similar to that of adults, but it was recognized that considerable interindividual variation in the disposition of pirarubicin and doxorubicin exists.

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