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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ラットに¹⁴C-meloxicalnを1mg/kgの用量で1日1回反復経口投与したときの吸収，分布および排泄について検討した．比較のために1mg/kgの用量で単回投与試験も実施した．
1．雄ラットに静脈内投与したとき，血漿中放射能濃度は分布相において速やかに消失した後，半減期(t_1/2)15.5時間で比較的緩やかに消失した．
2．雄ラットに経口投与したとき，血漿中放射能濃度は4時間から10時間にかけてほぼ一定濃度を維持するピークを示した．C_maxは3.23μg eq./ml，t_1/2は14.5時間であった．吸収率は68.6%であった．
3．雄ラットに経口投与したとき，放射能濃度は消化管，肝臓，血漿，全血および腎臓，ついで肺，甲状腺および心臓で高かった．ほとんどの組織中放射能濃度は投与後4時間で最高となり，その後低下した．脳および血球中の放射能濃度は非常に低かった．雌ラットでは投与後48時間の放射能濃度が雄ラットよりかなり高かった．
4．雄ラットに経口投与後，56.7%が尿中へ，39.0%が糞中へ排泄された．静脈内投与後の胆汁中排泄率は19.8%であった．雌ラットでは尿糞中排泄および胆汁中排泄ともに雄ラットより遅かった．
5．雄ラットに反復経口投与したとき，血漿中放射能濃度は3日目にほぼ定常状態に達した．反復経口投与により本薬の薬物動態は変化しなかった．
6．7日間雄ラットに反復経口投与したとき，体内分布パターンは単回投与時と類似していた．最終回投与後168時間の放射能濃度は甲状腺ではやや高かったが，ほとんどの組織で4時間値の約1/60以下に低下していた．尿糞中排泄率は単回投与時と類似していた．

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妊娠13および18日目の雌ラットに¹⁴C-meloxicamを経口投与し，胎盤通過性について検討した．胎児全身および胎児組織中放射能濃度は母ラットの血漿中放射能濃度より低かったが，時間とともに上昇した．妊娠18日目のラットでは胎児および羊水中放射能濃度が妊娠13日目のラットより高かった．
胎児へ移行した放射能の消失は非常に遅かった．

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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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1) KBT-3022経口投与後のラット糞を用いて未変化体およびM1～M12の12種の代謝物のうち，未変化体およびM3，M5，M6，M9の4つの主要代謝物の構造を合成標品とのスペクトルデータの比較で構造決定した．また，マウス肝臓中代謝物の検討結果よりM8はM9のグルクロン酸抱合体であると推定できた．
2) KBT-3022はM9に代謝された後，チアゾール環の4位または5位，もしくは両方のメトキシフェニル基のメチル基が脱離しM3，M5，M6が生成し，さらにグルクロン酸抱合または硫酸抱合等の抱合化反応を受けるものと推察された．
3) チアゾール環の4位および5位のメトキシ基の脱メチル化代謝に種差があり，マウス，イヌでは脱メチル化代謝がラットに較べ遅いことがわかった．
4) ヒトでは血漿中にM3，M5，M6は認められず，非抱合体のM9のみが認められた．また尿中にもM9が多く認められたことから，ラットよりもマウスに近い代謝を受けるのではないかと考えられた．
5) ラット，マウス，イヌ，ヒトとも代謝物の尿中への排泄率は低く，KBT-3022は主に胆汁を介し糞中に排泄されるものと考えられた．

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