The distribution of a ³H-labeled chemically modified antitumor β-glucan, grifolan NMF-5N (I/B), in various tissues after an injection into mice was examined in order to obtain information on distribution of the parent antitumor β-glucan, grifolan NMF-5N. Grifolan NMF-5N was treated with sodium metaperiodate and sodium borotritide to obtain tritium-labeled grifolan NMF-5N [³H-grifolan (I/B)]. When ³H-grifolan (I/B) was administered into normal mice by intraperitoneal (i.p.) or intravenous (i.v.) injection, radioactivity was detected in various mouse tissues. Next, ³H-grifolan (I/B) was injected into tumor-bearing mice 7 d after the tumor inoculation, which is the most effective administration timing for the antitumor effect of grifolan NMF-5N. The results indicated a strong radioactivity in spleens and tumor masses. These results suggested a close relationship between the antitumor activity and the distribution of grifolan NMF-5N in mice.

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The present study describes quantitatively the pharmacokinetics of the antibacterial agents, of loxacin and NY-198 (quinolonecarboxylic acid derivatives), in the central nervous system in rats by physiological modeling of the penetration, distribution and sequestration processes. The simulation curves corresponded well with the observed concentrations in the cerebrospinal fluid (CSF) and various brain regions after intravenous bolus administration. The estimated cerebrovascular diffusion clearances were considerably small compared with reported serum flow rates and similar among the brain parenchymal tissues examined. The distribution volume of each drug in each brain region was almost the same as the brain extracellular space (15 to 25% of the wet weight). It was also found that the K_p values of these drugs were similar among the various brain regions. These lines of evidence suggest that the antibacterial agents, ofloxacin and NY-198, localized only in the brain extracellular space and exhibited little region-specificity in distribution into the brain. Moreover, it was suggested from unexpectedly low CSF : serum concentration ratios after intravenous administration that these quinolones, which once diffused into CSF, could be sequestrated from CSF to blood via some transport system.

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The oral mucosal absorption of human calcitonin (HCT) was investigated in rats. Enhanced absorption of HCT was observed by coadministration of additives such as sodium deoxycholate, sodium tauroglycocholate, quillajasaponin (Quillayanin P-20^[O!R]), sodium lauryl sulfate, sodium myristate and sugar esters. The contribution of sugar esters to oral mucosal absorption of HCT was studied in some detail. The addition of a sugar ester having a hydrophilic-lipophilic balance value between 11 to 16 was found to be effective in increasing the absorption of HCT. Furthermore, it suggested that the type of constituent fatty acid of sugar ester was one of several important factors for the promotion of the oral mucosal absorption of HCT.

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The factors that causes age-dependent changes in phenytoin tissue and serum protein binding in rats were studied. It was confirmed that the age-dependent changes in the concentration of tissue constituents to which phenytoin bound mainly governed the change in phenytoin tissue binding. The concentration of the tissue constituents, protein and phospholipid, was changed by the water content in tissues in the growth process of rats. The increase in serum protein binding of phenytoin in the growth process of rats was caused by changes in both serum albumin concentration and binding parameters of phenytoin to serum albumin. The changes in binding parameters of phenytoin to serum albumin were led by those in the molar rations of free fatty acids to albumin.

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A radioimmunoassay was developed for a new, potent inhibitor of angiotensin-converting enzyme (ACE, EC 3.4.15.1), calcium (-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl) thio]-2-methylpropionyl]-L-prolinate (MC-838, altiopril calcium). The antiserum was obtained by immunizing rabbits with MC-838-bovine serum albumin (BSA) conjugate. MC-838-L-tyrosine labeled with ¹²⁵I and purified by thin-layer chromatography was used as a tracer. The assay sensitivity was 0.1 ng/ml, the average intra-assay coefficient of variation was 7.9%, and the average inter-assay coefficient of variation was 13.7%. The antiserum was specific for MC-838, showing only slight crossreactivity with degradation products of MC-838. After a single oral dose of MC-838 (2 mg/kg), radioimmunoassay of MC-838 canine serum demonstrated rapid absorption from the gastrointestinal tract with a peak level of 40.6 ng/ml. The decline in serum concentration was a biphasic decay, with a half-life of 80 min during rapid falloff followed by a slower decline.

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Male and female animal models of diabetes were prepared by treating rats with streptozotocin (STZ). Trimethadione (TMO) metabolism was depressed in male but increased in female diabetic rats. The insulin treatment normalized rats of both sexes. Serum dimethadione/TMO ratios at 2 h correlated with the elevated blood glucose levels in male and female control, the STZ-induced diabetic and the insulin-treated diabetic rats. Treatment with STZ in male rats affected the metabolism of antipyrine, decreasing urinary excretion of norantipyrine (NORA) urine but increasing elimination of 4-hydroxyantipyrine (OHA). In female diabetic rats, the amounts of the three major metabolites, NORA, OHA and 3-hydroxymethyl-3-norantipyrine and the total (conjugate + free) were increased compared to the control. In the insulin-treated groups, these changes were normalized. In conclusion, our study showed that the effect of STZ-induced diabetes on drug metabolism varies with the sex and the drugs used. Insulin normalized all these diabetic changes.

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The changes in lipid peroxide concentrations in plasma and tissues after subcutaneous administration of clioquinol to clioquinol-sensitive (S-rats) and -resistant neonatal rats (R-rats) were investigated. When a fixed dose of 150 mg/kg/d of clioquinol was given to R-rats for 14 d after birth, no significant difference in lipid peroxide concentrations in plasma, liver, kidney, brain and spinal cord at 5, 10 and 15 d was observed between clioquinol-treated and untreated rats. However, with increasing doses of clioquinol to R-rats every 5 d (150→300→600 mg/kg/d), the lipid peroxide concentrations at 15 d were higher in plasma, brain and spinal cord of clioquinol-treated rats than in those of untreated rats. These results suggested that repeated administrations of large doses of clioquinol to rats increased the lipid peroxides in nerve tissues. With S-rats at 5 d after birth, the lipid peroxide concentrations in liver were approximately twice those in R-rats regardless of the clioquinol administration.

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Using a radioactive microsphere method, the effects of hydralazine and a new antihypertensive vasodilator, pinacidil, on systemic and regional hemodynamics were examined and compared in conscious Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single intravenous administration of pinacidil decreased mean blood pressure in a dose dependent fashion (0.03-0.3mg/kg), and the peak effect was observed within a few minutes after administration. The onset of the hypotensive action of hydralazine was relatively slow compared to that of pinacidil, and its peak effect appeared 5-10 min after administration. There was no difference between WKY and SHR in the time course of blood pressure change, but the pressure reduction in WKY was less than that in SHR. We observed regional hemodynamic differences between the normotensive rats and the hypertensive rats. The flow rates in the kidney, spleen, gastrointestinal tract and skin of SHR were significantly lower than those of WKY. The intravenous infusion of pinacidil at a rate of 0.06 mg/kg/min increased cardiac output and heart rate, and selectively increased flow rates in organs with low flow rates compared to normotensive controls except for the spleen. Thus, pinacidil reduced total peripheral resistance of SHR to levels of WKY and normalized hemodynamic abnormalities in SHR. The regional hemodynamic action of pinacidil in SHR was not qualitatively different from that of hydralazine except in a few organs.

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Salivary excretion of 5-fluorouracil (5-FU) was investigated during constant rate intravenous infusion (0.306 mg/kg/min) in three male beagle dogs. Parotid (Pr) and mandibular-sublingual (MS) saliva were collected separately by stimulating salivation with 10% citric acid. After the start of 5-FU infusion, plasma and salivary 5-FU concentration increased rapidly to approach their steady state levels. There was a significant correlation between each saliva and plasma 5-FU concentration (p<0.01). The saliva/plasma drug concentration ratio (S/P ratio) and salivary pH were significantly higher in Pr than in MS saliva (p<0.001), similar to the results following bolus intravenous administration of 5-FU in beagle dogs. Both S/P ratio and salivary clearance increased with time before steady state. Thereafter, these values approached almost constant levels and their fluctuations became smaller than those following the bolus intravenous administration. These results showing S/P ratio and salivary clearance of 5-FU were affected by the plasma drug concentration, suggested the possibility that non-linear pharmacokinetics may be involved in the salivary excretion of 5-FU.

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To predict the plasma concentrations after percutaneous application of valproic acid (VPA), we presented a new pharmacokinetic model which includes simultaneous two absorption processes through the skin. The simulation contains four first-order rate constants for the following : a) absorption via the lipid and water routes in skin and b) uptake from the skin into systemic circulation and subsequent elimination. The fitness of the model presented for experimental data was compared with simple one-compartment models. As a result, the new model was successfully able to describe the time course of the plasma VPA concentrations following percutaneous application of the ointments. VPA was found to be rapidly absorbed across the water routes (k_al=2.60 h^-1), which accounted for about 70% of the total, followed by a lasting absorption via the lipid routes (k_a2=0.108 h^-1). The pharmacokinetic model with parallel lipid and aqueous pore skin transport pathways in skin was more adequate for the interpretation of p.c. absorption data of VPA than the models with an absorption process.

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Both ginseng total saponins (GTS) and one of its constituents, protopanaxatriol saponins (PT), inhibited the electrically evoked contractions of guinea-pig ileum (GPI) in a concentration dependent manner in a range of 1-100 μg/ml, and this effect was irreversible at high concentrations of the saponins. Protopanaxadiol saponins (PD) had a transient and weak effect. On the other hand, in mouse vas deferens (MVD), the contractions were increased by PT and PD, however, GTS was almost without effect. The inhibitory effect of morphine was arithmetically increased by pretreatment with 100 μg/ml of these saponins in GPI preparations, while the inhibitory effect of the contractions was potentiated in MVD preparations. Neither the inhibition of contractions in the GPI preparation nor the facilitation of contractions in the MVD preparation by these ginseng saponins was reversed by 1 μM naloxone, in contrast to naloxone antagonism of morphine-induced contractions in both preparations. GTS and PT caused a dose-dependent inhibition of BaCl₂-induced contraction of GPI. It is concluded that the mechanism on the inhibitory or faciliated effect of ginseng saponins on electrically evoked contractions in GPI and MVD preparations may be separated from the effect of opioids, and the mechanism may be based on the direct action of the saponins on smooth muscles preparations.

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A sensitive and specific radioimmunoassay has been developed for the determination of L-6-keto-piperidine-2-carbonyl-L-leucyl-L-proline amide (RGH-2202), a new analog of thyrotropinreleasing hormone (TRH), in plasma. An antiserum was produced in guinea pigs immunized with RGH-2202 which was conjugated to bovine serum albumin by an N-succinimidyl ester method. Iodine-125 labeled L-6-keto-piperidine-2-carbonyl-L-leucyl-L-prolyltyramine ([¹²⁵I] RGH-2202) was used as a tracer. Polyethylene glycol was used to separate bound and free [¹²⁵I] RGH-2202 in the reaction mixture. The assay of RGH-2202 in plasma was possible over a concentration range from 0.1 to 6.4 ng/ml, using 0.1 ml of plasma without the need for an extraction procedure. The antiserum used for the assay was highly specific for RGH-2202, and did not cross-react with TRH and the hydrolyzed derivatives of RGH-2202 such as L-6-keto-piperidine-2-carbonyl-L-leucyl-L-proline, L-6-keto-piperidine-2-carbonyl-L-leucine and L-leucyl-L-proline amide, which were assumed to be present in plasma as metabolites. The coefficients of variation were 4.6-6.7% for within-assay and 6.0-8.8% for between-assay. Plasma levels of RGH-2202 in rats were determined after an intravenous administration of RGH-2202 at a pharmacologically effective dose (0.625 mg/kg).

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