The absorption, metabolism and excretion of nucleoside analogue, lamivudine, were investigated after a single oral administration of ³H-lamivudine to rats at a dose of 2 mg/kg.
1. The total radioactivity in plasma reached the maximum at about 1 hour after oral administration, and declined rapidly with a half-life of about 2 hours. The absorption of ³H-lamivudine after oral administration was slightly decreased by feeding. ³H-lamivudine was well absorbed in each site of small intestine but not stomach.
2. The concentrations of unchanged drug in plasma reached the maximum within 1 hour after oral administration of lamivudine at 2 mg/kg, and declined rapidly with a half-life of about 1 hour. The bioavailability accounted for 81.9% and 76.7% in male and female rats, respectively. Significant linearity of AUC was observed at the dose range of 2 to 10 mg/kg in male rats.
3. The excreted radioactivity in male and female rats was 69.3% and 74.1% of the dose in urine and 29.1% and 23.7% in feces, respectively, up to 168 hours after oral administration. The majority of the dosed radioactivity was excreted into urine within 24 hours post dose. Less than 1 % of the dose was recovered in the bile within 48 hours post dose.
4. Radio-HPLC analysis of the collected urine indicated that virtually all of the radioactivity in the urine consisted of the unchanged lamivudine.

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The tissue distribution, transfer into fetus and milk of nucleoside analogue, lamivudine, were investigated after a single oral administration of ³H-lamivudine to rats at a dose of 2 mg/kg. Plasma protein binding and distribution to erythrocytes of lamivudine were also examined.
1. The radioactivity in most of tissues reached maxima at the first sampling time of 1 hour after oral administration to male rats and the concentrations in ileum, kidney and jejunum were higher than those in other tissues. The levels of radioactivity in most of tissues were below detection limit at 24 hours post dose.
2. The levels of radioactivity in the fetal whole body and tissues were less than 14% of that in the maternal plasma at 1 hour after oral administration to pregnant rats, and were below detection limit up to 48 hours post dose.
3. The radioactivity in milk after oral administration to lactating rats was 5-15 times higher than that in plasma from 4 to 24 hours post dose but it was eliminated rapidly in parallel with those in plasma.
4. The ratio of plasma protein binding and distribution to erythrocytes of ³H-lamivudine in rats, dogs and human was below 7% and 35-48%, at the range of 0.01-10 μg/l in vitro.
5. The ratio of plasma protein binding and distribution to erythrocytes of radioactivity was below 11% and 45-52%, after oral administration of ³H-lamivudine to male rats.

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The absorption, metabolism and excretion of nucleoside analogue, lamivudine, were investigated after a single oral administration of ³H-lamivudine to male and female dogs at a dose of 2 mg/kg.
1. The total radioactivity in plasma reached the maximum at 0.9 hour after oral administration to male dogs and declined rapidly with a half-life of 2.9 hours. The concentrations of lamivudine in plasma reached the maximum at 0.8 hour after oral administration and declined with a half-life of 1.4 hours. Profiles of the plasma levels of total radioactivity or lamivudine in female dogs were similar to those in male dogs.
2. The ratio of plasma protein binding of radioactivity was below 17% and the ratio of distribution to erythrocytes of radioactivity was 35-38%, after oral administration to male dogs.
3. The excreted radioactivity in urine and feces was 85.3% and 9.5% of the dose in male dogs, respectively, 93.2% and 5.8% in female dogs within 168 hours after oral administration.
4. Lamivudine and two major metabolites, trans-sulphoxide of lamivudine and cytosine, were observed by the radio-HPLC analysis of urine collected from male and female dogs after oral administration.

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Absorption, distribution and excretion of ¹⁴C-meloxicam were investigated in rats after repeated oral administration at a dose of 1 mg/kg once a day. For comparison, single administration studies were performed at a dose of 1 mg/kg.
1. After intravenous administration to male rats, plasma levels of radioactivity decreased rapidly in the distribution phase, then relatively slowly with a half-life (t_1/2) of 15.5 hr.
2. After oral administration to male rats, plasma levels of radioactivity showed a plateau spreading from 4 hr till 10 hr. The C_max was 3.23 μg eq./ml, and t_1/2 was 14.5 hr. The absorption was 68.6% of dose.
3. After oral administration to male rats, the levels of radioactivity were high in the gastro-intestinal tract, liver, plasma, blood, and kidney followed by the lung, thyroid gland, and heart. In most tissues the maximal levels were observed at 4 hr, then decreased. The radioactivity in the whole brain and blood cells was very low. Female rats showed much higher levels than male rats at 48 hr.
4. After oral administration to male rats, 56.7 and 39.0% of dose were excreted into urine and feces, respectively. Biliary excretion after intravenous administration was 19.8% in male rats. Female rats showed slower urinary, fecal, and biliary excretions than male rats.
5. After repeated oral administration once a day to male rats, mean plasma levels almost reached a steady-state on day 3. Pharmacokinetics was not influenced by repeated oral administration.
6. After repeated oral administration for 7 days to male rats, the tissue distribution pattern of radioactivity was similar to that after single administration. While the thyroid gland showed slightly high concentration 168 hr after the last dose, the levels of radioactivity in most tissues became below about 1/60 of those at 4 hr. Excretion balance was similar to that after single administration.

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Placental transfer of radioactivity was investigated after oral administration of ¹⁴C-meloxicam to the 13th- and 18th-day pregnant rats. The radioactivity levels in the whole fetus and fetal tissues increased with time, though the levels were lower than the maternal plasma levels. The 18th-day pregnant rats showed higher levels of radioactivity in the fetus and amniotic fluid than the 13th-day pregnant rats.
The radioactivity was very slowly eliminated from the fetus.

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The population pharmacokinetics (population PK) of ramatroban, a new thromboxane A₂ receptor antagonist, was studied in 280 subjects, including healthy volunteers and patients with bronchial asthma and perennial allergic rhinitis. In the single-dose studies, the healthy subjects were given ramatroban tablets in doses of 25 mg to 150 mg, and in the multiple dose studies of 50 mg to 100 mg twice a day for nine days. In the clinical studies in patients, the subjects were given ramatroban tablets in doses of 50 mg to 100 mg twice a day for several weeks, and the pharmacokinetic screening was conducted. Two or three samples per patient were drawn at randomized sampling time in steady state. A total of 1, 922 ramatroban plasma concentrations were obtained. The influence of concurrent drug administration, age, meals and some clinical laboratory values (GOT, GPT, total bilirubin, BUN and serum creatinine) on the pharmacokinetic parameters of ramatroban were examined by using a nonlinear mixed effect model (NONMEM), a computer program designed for population PK analysis, and on one-compartment open model with three parameters: total body clearance (CL), apparent volume of distribution (Vd/F) and absorption rate constant (Ka).
The final estimated model equations were as follows,
CL(L/hr)=0.694×BW×T-Bil^-0.220×0.789^Age×0.613^Theo
Vd/F(L)=3.42×BW
Ka(1/hr)=1.22
(BW: body weight, T-Bil: total bilirubin, Age: Age=1 if age≥65 years; Age=0 if age<65 years, Theo: Theo=1 if theophylline was co-administered; Theo=0 if theophylline was not co-administered)
The estimates of inter-individual variabilities were 37.1% in CL, 55.4% in Vd/F and 147.6% in Ka as a coefficient of variation. The residual variability was 63.40%.
Population PK is concluded to be useful for provi ding the current pharmacokinetic information in the premarketing stage. Population PK approach may improve the dosage guideline of ramatroban by co-analyzing with the postmarketing data in future.

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The metabolism of a new antiplatelet agent, ethyl 2-[4, 5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate (KBT 3022), was studied in rats, mice, dogs and humans. We found 12 metabolites (M1-M12) after oral administration of KBT-3022 in rat's feces and bile, and identified M3, M5, M6 and M9. After KBT-3022 was hydrolyzed to M9, the demethylation of the methoxyphenyl groups in 4-or/and 5-positions of thiazol ring of M9 resulted in the formation of M3, M5, M6. Furtheremore, these metabolites may be conjugated to glucuronides or sulfates. M8 is probably a glucuronide of M9 as revealed by the results of treatments of with β-glucuronidase. There is the species difference in the rate of the demethylation, the rate of the demethylation in mouse and dog was slower than that in rat. In human, the unconjugated M9 was only detected in plasma, similarly as in mouse, while the unconjugated M9 and glucuronides of M3 and M5 were found in urine. Urinary excretion of the metabolites accounted for 0.32% of dose in human.
We considered that the metabolism of KBT-3022 in human was close to that in mouse.

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