Disposition and metabolism of [¹⁴C]bermoprofen were studied in rats after oral administration mainly at the dose of 3 mg/kg.
It was suggested that bermoprofen was absorbed from the whole region of small intestine. The extent of gastrointestinal absorption was estimated to be virtually complete based on the ratio of urinary excretion of radioactivity after oral/intravenous administration. Blood level reached the maximum of about 2.0 μg eq./ml at 30 min after oral administration and decreased with the half life of 2.6 hr.
Maximum concentrations in most tissues were reached at 1 hr after oral administration. The kidney had the highest level of radioactivity, which was about 2.8 times higher than that in the plasma while the liver, was 0.69 of plasma. Other tissue levels were <1/3 of plasma level. Drug concentration in the central nervous systemwas the lowest. Fetal and milk levels were 0.07 and 0.18 of plasma level in pregnant and lactating rats, respectively. The extent bermoprofen of binding to serum proteins was 99.6%.
Approximately 70 % and 30 % of radioactivity were excreted in urine and feces, respectively, after oral or intravenous administration. About 46 % was excreted in the bile of rats with biliary fistula, of which about 46 % were re-absorbed when the radioactive bile was abministered to another rat.
Bermoprofen was known to be metabolized mainly by oxidation of methyl group, reduction of carbonyl group and conjugation at propionyl group, and the first biotransformation pathway was found to be predominant in rats.

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Absorption, distribution, metabolism and excretion of [¹⁴C] bermoprofen were studied in rats during and after ten consecutive daily oral dosings at 3 mg/kg.
During the experimental period, blood levels were in the range of 1-2 μg eq./ml at 1 hr after each administration and decreased with the half life of 4.6 hr after the last administration. After the last administration, all tissue levels were similar to those at 1 hr after single administration. With exception for a low levels in some tissues like the kidney and liver, radioactivity in most tissues was no more detected at 96 hr after the last administration. Excretion of radioactivity in urine and feces was approximately 65 % and 45 %, respectively, during experimental period. Composition of plasma and urinaly metabolites after the repeated administration were similar to those after the single administration. As above, disposition and metabolism of [¹⁴C] bermoprofen were unaltered by repeated administration under present conditions.

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Disposition and metabolism of [¹⁴C]bermoprofen were studied in cynomolgus monkeys after oral administration at the dose of 1 mg/kg.
Plasma level reached the maximum at 2 hr after administration and decreased with apparent half life of 2.1 hr. The extent of gastrointestinal absorption was estimated to be virtually complete based on the ratio of urinary excretion of radioactivity after oral/intravenous administration.
After per oral administration, approximately 76% and 22% of radioactivity were excreted in the urine and feces, respectively. About 38% of radioactivity were excreted in the bile of animals with biliary fistula, whose 63% was reabsorbed: the enterohepatic circulation should be >24% of dose.
Bermoprofen was known to be metabolized mainly by oxidation of methyl group, reduction of carbonyl group and conjugation at propionyl group, and the second biotransformation pathway was found to be predominant in monkeys.

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Effect of aluminum hydroxide on the pharmacokinetics of new quinolones, ofloxacin, enoxacin and norfloxacin, was investigated in cross-over study using five healthy male volunteers. Serum levels of the three drugs were decreased significantly up to 10 hours later by the concurrent administration of aluminum hydroxide. Cmax and AUC of the respective drug were decreased significantly by combined administration with aluminum hydroxide. Urinary excretion rates of the drugs within 24 hours were also decreased significantly by the concurrent administration of aluminum hydroxide. This combination effect of aluminum hydroxide on the pharmacokinetics of new quinolones was largest in case of norfloxacin and smallest in ofloxacin. Thus, these results suggest that the combination effect of aluminum hydroxide may be induced by the inhibition of absorption of new quinolones in the gastrointestinal tract.

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Absorption, distribution and excretion of omeprazole, a potent antiulcer agent, were investigated in rats after oral administration of ¹⁴C labeled compound (¹⁴C-OPZ).
Urinary and fecal recoveries of radioactivity (¹⁴C) within 4 days at a dose of 5 mg/kg were about 22% and 72% after po dose, about 32 % and 66 % after iv dose, respectively. In male rats, urinary excretion had a tendency to increase under the fasting condition and the higher dose levels.
About 48 % of dose was excreted in the bile of male rats during 30 hours after oral dose of 5 mg/kg, and about 26 % of ¹⁴C excreted in the bile was reabsorbed from the intestines due to enterohepatic circulation.
Peak plasma levels of ¹⁴C was reached within 0.5 hour, and the radioactivity was eliminated with the terminal half-lives (T_1/2) of 23.1 ?? 30.9 hours after oral dose. A significant increase in Cmax and AUC's was found, exceeding the expected values proportional to administered dose.
High levels of ¹⁴C were observed in the liver, kidney, urinary bladder and gastrointestinal tracts, but there was no evidence of an accumulation of ¹⁴C in any tissues after oral administration. Tissue distribution pattern of ¹⁴C in female rats was similar to that in male rats. The level of ¹⁴C in the milk of lactating rats was slightly higher than that in the plasma. The level of ¹⁴C in the placenta and tissues in fetuses was lower than that in the maternal blood or plasma.
No significant quantitative and qualitative differences in urinary metabolite pattern were observed among dose levels, but a slightly quantitative difference was observed between males and females.

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The binding of quinidine disopyramide and lidocaine to purified human α₁-acid glycoprotein (AAG-P) was studied using ultrafiltration. These drugs bound to a single class of binding site of AAG-P which was characterized by higher affinity (Kd for quinidine was 7.1×10^-8M, for disopyramide 1.2×10^-6M and for lidocaine 2.0×10^-5M) than that of human serum albumin (HSA). The percent of binding of disopyramide and lidocaine to AAG-P and HSA were mainly related with the concentration of AAG-P.

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Conventional whole-body autoradiography (MAR) shows detailed tissue distribution of radioisotopes “relatively”, not “quantitative”. We attempted to establish quantitative analytical method for MAR (QMAR) using computer-assisted densitometry system introduced from Dr. Sokoloff's laboratories, N.I.H. and Imaging-plate system developed by Fuji Photo Film Co., Ltd.
Autoradiograms were prepared from rats after administration of (CH₃-¹⁴C) FO-1561 (S-adenosylmethionine sulfate tosylate, SAMe) and exposed on X-ray films (Kodak, SB-5) for 3.5 days or Imaging-plates for 1.5 hrs with ¹⁴C-staircases. Measurement of isotope concentration was done from the autoradiograms by comparing optical densities or detection intensities of the regions of interest with a series of standards. Concentrations of SAMe-¹⁴C in blood, muscle, thymus, submaxillary gland and brain obtained from QMAR methods were comparable to those obtained from conventional tissue dissection method (LSC).
Correlation coefficient between QMAR and LSC method was lager than 0.9. In addition, quantitative information was obtained on the distribution in such small organs which can not be dissected or on the localization of radioactivity in organ or tissue.

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Cibenzoline, a new antiarrhythmic drug, was studied in five healthy male volunteers to evaluate its steady-state pharmacokinetics after oral dosing. The subjects were given a single dose of 150 mg of cibenzoline succinate, followed three days later by 150 mg three times a day at 9 am, 2 pm and 7 pm on day 1 to day 7, and once at 9 am on day 8.
The plasma and urinary concentrations of cibenzoline and its dehydro metabolite were determined by high performance liquid chromatography.
The plasma half-life of cibenzoline after the last dose of multiple dosing (6.56 hr) was longer than that after single dosing (5.12 hr), whereas urinary half-life estimated from urinary excretion rates was actually the same for single dosing (6.40 hr) and multiple dosing (6.49 hr). The percent of the given dose recovered in the urine during multiple dosing (73.9 %) was higher than that during the first 48 hours after single dosing (48.9 %).
The plasma concentrations of cibenzoline obtained each from single and multiple dosing were well fitted to a two-compartment model with zero-order absorption. The model-dependent analysis showed a 22 % decrease in total clearance by multiple doses. This is mainly due to a 54 % decrease in extra-renal clearance. The decrease in clearance was suggested to be transient, and the trough plasma concentrations and urinary excretion rates reached steady state on the second day of multiple dosing.
The maximum plasma concentration of dehydro metabolite after single dosing was about 1/20 times that of cibenzoline, and was nearly the same as that after multiple dosing. The trough plasma concentrations of the metabolite reached steady state after the first dose of multiple dosing.
Cibenzoline was well tolerated. Clinically significant adverse effects attributable to the drug were not observed.

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The pharmacokinetics of cibenzoline, a new antiarrhythmic drug, were examined in healthy male volunteers. In a Latin Square, three-way crossover design, six subjects in three groups of two were given single 100-, 150-, or 200-mg oral doses of cibenzoline succinate in a fasting state.
The plasma and urinary concentrations of cibenzoline and its dehydro metabolite were determined by high performance liquid chromatography.
Cibenzoline plasma concentrations declined in a biexponential manner after reaching the maximum plasma concentrations. The mean±standard deviation maximum plasma concentrations of 201±39, 311±43, and 478±120 ng/ml were attained from 1 to 2 hours after doses of 100, 150, and 200 mg, respectively. The elimination half-life was dose-independent and averaged 5.47±0.59 hours. The maximum plasma concentration and the area under the plasma concentration-time curve increased in proportion to the dose. The maximum plasma concentrations of dehydro metabolite were very low and were about 1/20 times or less than those of cibenzoline. The average of 58.9±11.2 % of the given dose was excreted as cibenzoline dose-independently in the urine and only 1.13±0.55 % as dehydro metabolite.
Besides the above model-independent pharmacokinetic parameters, model-dependent parameters were also obtained by curve-fitting the plasma data to a two-compartment model with zero-order absorption.
Cibenzoline was well tolerated by all subjects. Clinically significant adverse effects were not observed.

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There is increasing evidence demonstrating time-dependent changes in effectiveness and toxicity of several agents. Recently we investigated some chronopharmacological aspects of antihypertensive agents such as diuretic, adrenoceptor blocking and calcium channel blocking. We observed that the effects of diuretic agent are greater when it is administered at the rest period than when it is administered during the active phase. On the contrary, the effectiveness as well as toxicity of adrenoceptor and calcium channel blocking agents are greater following administration at the active period. In this minireview, the chronopharmacolgical profiles of antihypertensive agents are summarized in detail.

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The specificity and sensitivity of hapten immunoassays, especially enzyme immunoassay for steroids, are described. In the production of antibodies to a steroid, the steroid portion of a haptenized immunogen binds to specific surface receptors of B lymphocytes, resulting in the proliferation and differentiation of the cells into plasma cells which secrete anti-steroid antibodies having the same antigen-recognition specificity as that of the receptor. Thus, the available specificities of antisteroid antibodies should be influenced by the position on the steroid molecule used for conjugation to a carrier protein and also by the stereochemistry of the steroid hapten. Various factors influencing the assay specificity or sensitivity are summarized: these are antibody nature, label enzyme, method of determining enzyme activity, enzyme labeling method, steroid/enzyme molar ratio in the label, and bridging phenomenon.
Production of monoclonal anti-steroid antibodies and development of new biotechnologies related to the modification of antibody specificity are also described.

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