We have performed in our department Phase I Studies on various drugs, ten of which were originally investigated in Japan. For these domestic drugs, preclinical animal studies concerning toxicology, teratology, general pharmacology, efficacy supporting, and pharmacokinetis are discussed herein. Most of the drugs were to be used in man for the first time, so the initial dose was carefully determined based upon the results of animal studies. The criteria for determination of initial are then presented and discussed. One of the ten drugs showed a marked difference in pharmacokinetics between animals and human. The Phase I Study on this drug is presented as an example.

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The pharmacokinetics of aspirin was investigated in healthy volunteers and patients who had undergone partial or total gastrectomy. Sixty-six persons participated in the study after verbal consent. Aspirin 5 mg/kg was given orally after an overnight fast, and blood samples were taken at 0.5, 1, 1.5, 2, 4, 6, and 9 hours after aspirin administration. Serum concentrations of salicylic acid were measured spectrophotometrically. For over 40% of the subjects the serum concentration-time curves were best described by a one-compartment model. In the gastrectomized group of patients there was significant reduction in the systemic clearace of aspirin, which resulted in a prolongation of the elimination half-life and an increase in the area under the curve.
The absorption kinetics of aspirin was virtually identical in the normal volunteers and the gastrectomized persons, with no significant age-related changes being noted in the pharmacokinetic parameters of aspirin (range: 44-62 yr; mean: 51 yr).

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A Phase I Study was carried out on disopyramide phosphate retard (slow-release) tablets in healthy Japanese subjects, employing Rythmodan^® capsules as the control drug. The safety and pharmacokinetics of disopyramide phosphate were investigated.
This study was carried out by the cross-over method: the subjects were first administered three doses (at 12-hour intervals) of disopyramide phosphate for each of the 150 mg, 200 mg, and 250 mg retard tablet preparations; they were then administered four doses (at 8-hour intervals) of Rythmodan^®, i. e., one 100 mg capsule each time. After that, using new subjects, a one-week multiple-dosing study was conducted on disopyramide phosphate, administering one 200 mg tablet every 12 hours.
As a result, no striking abnormalities were detected in terms of the subjective symptoms, vital signs, electrocardiogram (ECG), auscultatory percussion examination or laboratory tests. The peak serum concentration occurred 2 hours after the administration of one 100 mg capsule, 4-6 hours after the administration of one retard tablet, and at 4 hours in the case of multiple-dosing with retard tablets. The urinary excretion of the drug is slower in the case of three consecutive administrations of the retard tablets than four doses of the capsules, and the amount of excretion in the case of the retard tablets was reduced because of retention in the body until reaching a steady state. In the case of multiple-dosing of the 200 mg retard tablets for one week, a steady state was reached in about 3 days.
The above results confirmed the pattern of the serum concentration and the safety of disopyramide phosphate, administered in the form of 150, 200, and 250 mg retard tablets. It was therefore concluded that there are no impediments to the performance of Phase II Study on this drug preparation.

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Our group previously reported the time-of-day effect of oral administration on diazepam kinetics and its sedative action in healthy men. In these studies, it has been suggested that the absorption rate of diazempam from the gastrointestinal tract is faster in morning dosing than in evening dosing. The present study was performed to elucidate the mechanism of time-of-day effect on diazepam kinetics and dynamics, administering 5 mg diazepam (Cercine^® injectable solution) intravenously under the same experimental conditions as the oral dose study described above. Eight healthy volunteers participated in the study. The subjects received a 5-mg dose of diazepam intravenously at 9: 30 a. m. and after a 2-wk interval, at 9: 30 p.m., in a randomly assigned cross-over study. Meals were standardized in order to fit the subjects' usual meal amount. Plasma diazempam concentrations were determined by gas chromatography (ECD). Changes in subjective feelings such as “mentally slow”, “feeble”, “clumsy”, and “lethargic” were more marked in the morning trial at 0.5 hr after injection. More marked sedative effects were demonstrated in the morning trial by using the digit symbol substitutiontest and the continuous number addition test. Mean (±SD) total diazepam concentrations in plasma in the morning trial vs in the evening trial were: 218 (±15) vs 192 (±12) ng/ml at 0.5 hr after drug administration (0.05<P<0.1); 164 (±39) vs 132 (±16) ng/ml at 1 hr after injection (P<0.05). The results suggest that there exists time-of-day effect of intravenous injection with diazepam injectable solution onsedative actions and kinetics, which may be clinically important in some situations. Inaddition, the time-dependent kinetics of diazepam after oral dosing cannot be explainedonly by the absorption rate from the gastrointestinal tract, since intravenousadministration of diazepam did not eliminate the difference in total plasma diazepamconcentrations between morning and evening dosing at 0.5 hr and 1 hr after injection.

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Plasma concentrations of isosorbide-5-mononitrate (5-ISMN) (TY-10368) measured: (1) after oral doses of 10 mg at fasting or at 1.5 hr after meal in 3 subjects with one week between dosing sessions, (2) after oral doses of 10, 20 40 mg in 6 subjects and (3) after repeated oral doses of 20 mg at 12-hr intervals 84 hr in 6 subjects. Food intake reduced the peak plasma concentrations of ISMN, but did not affect the extent of bioavailability from oral dosing after an overnight fast. Maximum plasma concentrations were achieved within the same range time after all doses: an average of 1.7 hr±0.2 (SD; non-fasting). The pharmaco-kinetics showed dose-lineality, since the peak plasma concentrations and the total area under the curve (AUC) were proportional to dose administered. The elim ination half-lives after administration of all doses were in the range of 5-6 hr, with narrow interindividual variation. The total amounts of free and conjugated 5-ISMN excreted into the urine over 60 hr were proportional to dose administered within a range of 22-36%, and only a trace amount was detected at 24 hr after dose.
Repeated administration at 12-hr intervals during 84 hr did not increase the minimal plasma concentration or elimination half-life without significant increase of time to peak plasma concentration.
Whereas the diastolic blood pressure did not change systematically, average falls in the systolic blood pressure of 6.2%, 10.3% and 12.3% were observed at the time of the peak plasma levels after single oral dose of 10, 20 and 40 mg, respectively. There was no significant correlation between maximum plasma 5-ISMN levels and corresponding systolic blood pressure reduction.
The plasma cyclic GMP concentrations determined when the peak 5-ISMN plasma levels were achieved or when the maximal systolic blood pressure reductions were noted, decreased significantly after oral doses of 20 mg, but the highest dose did not change the plasma cyclic GMP levels significantly.
All subjects complained of a headache or felt heavy-headedness which did not seem to be dose-dependent, and mentioned no symptoms at 24 hr after TY-10368 administration.

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A newly developed calcium antagonist, FK 235, was orally administered to 16 healthy male volunteers in a single-dose and a 7 multiple-dose trial to investigate the pharmacokinetics and pharmacodynamics of this drug.
1. Single-dose trial
Clinical symptoms were encountered in subjects given 1mg or more, ascribed to dilatation of the peripheral blood vessels. FK 235 caused no clear effect on systolic blood pressure, but a dose-dependent decrease of diastolic blood pressure and increase of pulse rate after dosing with 2mg or more were seen.
FK 235 inhibited rise in total peripheral resistance in cold pressor test, and increased cardiac index at rest.
The area under the curve (AUC) after dosing with 8 mg was 25.6 ng·hr/ml and the elimination half-life was 1.4 hrs.
FK 235 had no effect on laboratory test values or ECG findings.
2. Multiple-dose trial
There were on other clinical symptoms except transient facial flush in one subject on the 2nd day.
Systolic blood pressure after dosing was not significantly lower than on the observation day, but diastolic blood pressure was significantly lower.
There were no abnormal laboratory test findings except an increase of transaminase in 2 subjects.

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Hemodynamic studies using radiocardiocardiography with radioactive iodinated human serum albumin [RIHSA] were performed in thirty-four patients with essential hypertension before and during treatment with oral arotinolol, bunazosin and prazosin, and these effects were compared with those in twenty-one patients treated with propranolol and labetalol in a previous study
α-Blockade with bunazosin and prazosin decreased systolic and diastolic blood pressure without any significant change in cardiac index (CI), and tended to reducetotal peripheral resitance index (TPRI). α, β-Blockade with labetalol tended to reduce heart rate and reduced TPRI without any change in CI. α, β-Blockade with arotinolol, which had weaker α-blocking activity than labetalol, reduced systolic and diastolic blood pressure, heart rate and CI, and increased TPRI. These effects appeared to be similar to those of β-blockade with propranolol . However, the increase in TPRI with propranolol was greater than that with arotinolol.
These results suggest that vascular β-receptor blocking action may play a part in increasing peripheral resistance, while the α-blocking action on vascular sites may induce vasodilating action with a resultant decrease in TPRI or minimize elevated TPRI with vascular β-blockade according to their potency of the α-blocking activity.

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