Absorption, distribution, excretion and metabolism of [¹⁴C]cadralazine were studied in normal male, and pregnant and lactating female rats after oral and/or intravenous administration at the dose of 3 mg/kg.
1. Cadralazine was found to be absorbed from the whole region of small intestine as it was shown in rats with ligations at the bile duct, pylorus and lower end of duodenum.
2. Plasma levels of radioactivity reached the maximum of about 1 μg eq./ml at 1 hr aftdr oral administration in normal rats and decreased with the half life of 1.8 hr. The ratio for AUC after oral/intravenous administration was around 0.9.
3. Drug concentrotion in most tissues reached the maximum at 1 hr after oral administration. The highest concentrotions were in kidrey and liver, most other tissue levels including the target aorta were virtually close to plasma level and brain level was the lowest. The rate of disappearance of radioactivity was slightly slower in some tissues such as aorta than that in plasma.
4. The level of radioactivity in fetus was lower than maternal plasma level. The level in the milk was slightly higher than in plasma.
5. The extent of protein binding was as low as about 20%.
6. About 86 % of orally administered radioactivity was excreted in the urine within 96 hr, and 6 % in the bile within 48 hr. The ratio of urinary excretions after oral/intravenous administration was about 0.9.
7. Major radioactive compound found in plasma and urine was the unchanged cadralazine. A few metabolites, including known ones, were found to be minor.

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Absorption, distribution, excretion and metabolism of [¹⁴C]cadralazine were studied in rats after 10 consecutive daily oral administration at the dose of 3 mg/kg.
1. Plasma levels at 1 hr after each administration were around 1 μg eq./ml. Levels after the last administration decreased biphasically with half lives of 2.4 and 12.5 hr.
2. At 1 hr after the last administration, drug concentration in erythrocyte was elevated 2.7 times in comparison to that after single administration but other tissue levels were virtually similar to those after single administration. At 24 hr, erythrocyte and liver levels were higher.
3. Urinary and fecal excretion amounted to about 93 and 8 % of administered radioactivity during and after repeated administration.
4. Composition of plasma and urinary metabolites was virtually similar to that after single administration and the unchanged cadralazine was the major component.

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For elucidation of common characteristics in disposition of hydralazine vasodilators, distribution of [¹⁴C]hydralazine and [¹⁴C]budralazine was studied in normal rats at the time points of their maximal tissue levels and at 24 hr after single and 10 consecutive daily oral administration and was compared with that of [¹⁴C]cadralazine. Doses were set to be virtually equipotent to each other from the aspect of their maximal antihypertensive activity. For comparison, following three parameters were used: tissue/plasma concentration ratios, the ratio of concentrations observed 24 hours after administration to maximal tissue concetration and tissue levels after repeated/single administration.
1. The distribution of the agents was commonly significat in liver and kidney being conceivably related with their disposition, and was rather selective to the possible target vasculature, aorta as a representative. The rate of disappearance of radioactivity seemed to be slower in common tissues: e.g., in erythrocytes, aorta, brain, lung, Harderian gland, thyroid and adipose tissue.
2. After repeated administration, the change in distribution pattern relative to that after single administration was significant in the following order of [¹⁴C]budralazine (increase of tissue concentration in aorta, erythrocytes, spleen and skin)> cadralazine (in erythrocytes)≥hydralazine (in adipose tissue). The rate of disappearance was slower in such commonn tissues which are rich in collagen content (e.g., aorta, skin, lung, trachea etc). Accumulation of radioactivity was significant in 12 tissues for [^14C]cadralazine, 13 tissues for [¹⁴C]hydralazine and 21 tissues for [¹⁴C]budralazine.

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Antimicrobial activities of Rokitamycin (RKM) in the urine were decreased extremely after the samples were stored at -20°C for a long time. Therefore, a reaction of macrolides with urine was studied under the condition of freezing at -20°C.
1. Each of RKM, Midecamycin acetate (MOM), Josamycin (JM) or other macrolides was added to human urine and stored at -20°C. Their antimicrobial activities in human urine were decreased to 12%-45% for 1 week and to 3%-22% for 8 weeks.
2. RKM in human urine was analyzed by thin-layer chromatography after storage at -20°C. It had been found that the amount of RKM was decreased and a new compound, which was more hydrophilic than RKM, was generated according to the decrease of its activity.
3. Each of RKM, MOM, JM or other macrolides was added to a 1.4 % (w/v) aqueous urea solution and stored at -20°C. Their antimicrobial activities in the urea solution were decreased in the same way as in human urine.
4. By the thin-layer chromatography analysis, it had been found that the amount of each macrolides was decreased and new compounds were generated.
5. From the Mass spectra and NMR spectra data, these new compounds were determined as macrolide-18-bis-urea adducts.
6. The bis-urea adducts were substantially hydrolyzed and converted into parent compounds after the heat treatment at 121°C for 15 minutes in the pH 4.5 solution.
7. Antimicrobial activities in the urine samples, which were collected from humans after oral administration of RKM and stored at -20°C for 8 weeks, were also recovered approximately 100% of the initial activities by the heat treatment.

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The absorption, distribution, metabolism and excretion of cefixime, an orally active cephem antibiotic, were studied in rat given the ¹⁴C-labeled drug intravenously or orally in solution.
After intravenous dosing, serum concentrations of the unchanged cefixime declined two-exponentially with respective half-lives of 0.31 and 1.33 hr. The total serum clearance and the volume of distribution at steady state were 1.68 ml/min/kg and 176 ml/kg, respectively. After oral dosing, the maximal serum concentrations of the unchanged cefixime were reached at 1 hr and declined with an apparent half-life of 2.46 hr. Oral bioavailability was 23 ?? 27%. Most of the serum radioactivity was from the unchanged cefixime regardless of dosing route. Radioactivity taken into the systemic circulation was rapidly disributed in the various tissues, and was high in the kidneys, urinary bladder, blood and liver. After intravenous dosing, excretion of radioactivity was 82 % of the dose in the urine and 22 % in the feces. Biliary recovery of radioactivity was 35 %. After oral dosing, excretion of radioactivity was 20 % in the urine and 85 % in the feces. Most of the radioactivity in the urine and bile after dosing by either route was in the form of the unchanged cefixime.

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Urinary metabolite profile of nilvadipine, a new dihydropyridine calcium antagonist, was examined in 6 healthy male volunteers given the drug in single and repeated oral doses. The drug was given first in a single oral dose of 4 mg, and after washout during three days or more, in 11 repeated oral doses of 4 mg twice a day. Nilvadipine and its 5 metabolites were determined in the urine by capillary column gas chromatography or high performance liquid chromatoqraphy. The unchanged nilvadipine was not detected in the urine after either the single or repeated dosings. In the urine collected during 32 hours after a single dosing, 3-carboxyl pyridine derivative of nilvadipine (M3) was excreted in 58.0% of the given dose and 5-carboxyl pyridine derivative in 3.3%. The excretion of the hydroxyl derivative of isopropyl ester moiety of M3 and the 5-carboxyl derivative of nilvadipine accounted for 2.4 and 1.6% of administered dose, respectively. The profile of the urinary metabolites after repeated dosing was similar to that after single dosing.

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Flurbiprofen (FP), nonsteroidal antiinflammatory drug, is poorly soluble in water and sometimes causes an adverse reaction due to a stimulant property to stomach after oral administration. The inclusion complexes of FP with natural β-and γ-cyclodextrin (β-, γ-CyD) or methylated β-CyD, heptakis(2, 6-di-O-methyl)-β-CyD (DM-β-CyD) and heptakis(2, 3, 6-tri-O-methyl)-β-CyD (TM-β-CyD), in a 1:1 molar ratio were prepared, and then their dissolution, absorption characteristics and the irritation of the gastric mucosa of rats were compared with those of FP. The dissolution rate of FP from capsules in JP XI No. 1 was significantly increased by the inclusion complexation (γ->DM-β->β->TM-β-CyD complex>FP alone). The serum levels of FP following the oral administration in form of complex to rats are higher than after the drug alone (DM-β-≈γ->β->TM-β-CyDcomplex> FP alone). The gastric damages induced by a single administration of complexes with β-, γ-and TM-β-CyD were less than that of FP alone, while gastric damage induced by DM-β-CyD complex was same as FP alone. The enhanced bioavailability and reduced gastric damage of FP by complexation with natural β-and γ-CyD suggested the possibility of smaller doses and fewer adverse effects in FP therapy.

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A radioimmunoassay method for the determination of glycyrrhetic acid (GA) was developed. The measurable range of GA varied from 0.195 to 25 ng/tube and favorable accuracy was observed throughout the range (CV ; 5.8% for triplicate). The radioimmunoassay method described in this paper was superior to another analytical method in terms of sensitivity and simplicity. The serum concentrations of GA in the portal vein and vena cava were investigated after oral administration of 2.6 mg/kg of glycyrrhizin (GL) in rats. C^max reached 575.5 ng/ml at 12 hr after administration in the portal vein, while it was 159.3 ng/ml at 18 hr in the vena cava. Serum levels of GA in both sites slowly decreased up to 34 hr, and approximately 200 ng/ml of GA was still maintained after 48 hr in the portal vein. Serum levels of GA in the vena cava was about 1/4 of that in the portal vein, suggesting first pass effect. AUC⁴⁸₀ in the portal vein and vena cava were 16628.5 ng·hr/ml and 3370.5 ng·hr/ml, respectively. This method may be useful for the pharmacokinetic studies of GA.

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The absorption site and route of ethyl-eicosapentaenoate (EPA-E), the effect of bile, and particle size and purity of EPA-E on the absorption and identity on the absorption between EPA-E and sodium eicosapentaenoate (EPANa) were investigated after oral administration of ¹⁴C-EPA-E or ¹⁴C-EPANa in rats and the following results were obtained.
1. Radioactivity was rapidly absorbed from the small intestine and only 4.6% of the administered radioactivity was recovered from the intestine and intestinal contents at 24 hr after dosing.
2. Radioactivity was mainly absorbed through a lymphatic route after oral administration of ¹⁴C-EPA-E.
3. The absorption of ¹⁴C-EPA-E was promoted by a supply with bile.
4. It was presumed that the smaller particle size of EPA-E, showed the greater the absorption.
5. It was thought that there is no significant difference in the gastrointestinal absorption between EPA-E and EPANa.
6. The absorption of EPA-E from the gastrointestinal tract was not influenced by purity of EPA-E.

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Plasma level, tissue distribution and excretion of ethyl eicosapentaenoate(EPA-E) were studied after oral administration of ¹⁴C-uniformly labelled EPA-E to rats and dogs and the following results were obtained.
1. The maximum concentration of radioactivity in plasma was obtained at 6-9 hr and at 24hr after dosing in rats and dogs, respectively. The elimination of radioactivity from plasma was biphasic.
2. The radioactivity administered to rats was mainly excreted in expired air.
3. The cumulative biliary excretion of radioactivity was 2.9 % of the dose within 24 hr.
4. The concentration of radioactivity in each tissue reached maximum at 9-24hr after dosing except for brain, fat, skin, muscle and aorta in which the concentration reached maximum at 1 week and subsequently decreased gradually. The elimination rate of radioactivity from each tissue was almost as same as that from plasma or a little slower.
5. Foeto-placental transfer of radioactivity in the pregnant rats at 12 and 19 days of gestation was observed but its extent was low.
6. The milk level of radioactivty in the lactating rats reached maximum at 24 hr and was 6-14 times higher than that in the maternal blood after 24hr.
7. Radioactive substances in plasma were mainly bound to plasma protein in rats and dogs.
8. During daily repeated administration to rats, the concentration of radioactivity in plasma at 24hr after every dosing reached plateau level within the 12 days but that in each tissue increased with increase in the number of doses.
No remarkable difference in elimination half-lives of radioactivity in each tissue between the single and repeated dosing was observed.

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The use of stable isotopically labeled drugs combined with gas chromatographymass spectrometry (GC-MS) has found a broad application in pharmacological studies. Initially, stable isotopically labeled drugs and metabolites served as the ideal mass internal standards for analytic procedures. However, their in vivo use has expanded and proved to be a powerful pharmacokinetic tool. This review article will emphasize the utilization of stable isotope methodology in studying the bioavailability/pharmacokinetic of drugs. The primary advantage of the isotopic methods is that the drug can be administered concomitantly either by two routes (e.g., intravenous and oral) or in two formulations (e.g., solution and solid dosage). Thus, a single set of blood samples serves to describe the time course to the routes or formulations being compared. The technigue is also well suited to “pulse”administration, wherein the kinetics of a single dose, during chronic dosing regimens, canbe examined. Another major advantage of the technique is that endogenous and exogenous compounds having the same basic structure can be differentiated by employing stable isotopically labeled analogs. I will attempt to outline the elements of study design for the application of stable isotope methodology.

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Many drugs are being developed for treatment of ventricular arrhythmias (VA) in myocardial infarction. However, the characters of excitation and conduction abnormalities change during the period of ischemia. Thus, these abnormalities should be clarified and the most effective drug should be chosen for the treatment of VA. In acutely ischemic myocardium of experimental animals, an alternation of ST-T comlex in ECG is observed, which is sssociated with VA. The causes of these VA are large injury currents as well as delayed conduction. The VA are prevented by the pretreatment of calcium antagonists, but not by class I antiarrhythmic drugs. In one day-old infarction, serious VA appeared, which are caused by abnormal automaticity in Purkinje fibers. These VA are inhibited by class I drugs. In one week-old infarction, VA are caused by reentry mechanism, which is prevented by the class I drugs. In one to three months-old infarction, reentry is hardly produced by premature stimulation. In these infarction, abnormal automaticity appeared in the border of non-infarcted and infarcted area, and the automaticity sometimes caused VA. Hypertension and diabetes mellitus enhance the abnormal automaticity. Hyperthyroidism enhances ischemia-reperfusion induced VA, which may be caused by enhanced abnormal automaticity. However, mechanisms of VA in old infarction and in other heart diseases should be further investigated, and effects of drugs on these VA remain to be clarified.

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