The absorption and excretion of ¹⁴C labeled Q-35[(±)-1-Cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid], a new fluoroquinolone antimicrobial agent, were studied in rats.
1. When ¹⁴C-Q-35 was administered orally at the dose of 20 mg/kg to fasted rats, the radioactivity was absorbed rapidly and reached a maximum plasma concentration (Cmax) at 0.38 h, thereafter was eliminated at a half-life of 2.84 h.
The AUC of the plasma radioactivity after an oral administration of ¹⁴C-Q-35 to nonfasted rats decreased to about half of AUC in fasted rats. It was suggested that there was a significant decrease in the extent of absorption by food.
2. It was suggested that ¹⁴C-Q-35 was absorbed from the upper and middle segments of small intestine but scarcely from the stomach as revealed by the loop method of the digestive tracts.
3. The urinary and fecal excretion rate of the radioactivity during 72 h after an oral administration of ¹⁴C-Q-35 to fasted rats were 42.2% and 56.5 % (total: 98.6%) of dose, respectively. It was suggested that the administered radioactivity was excreted in about 100% into the urine and feces.
4. The biliary excretion rate during 24h after an oral administration of ¹⁴C-Q-35 to nonfasted rats was 32.3% of the dose, and the quarter of the radioactivity excreted to bile was reabsorbed.

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The distribution of radioactivity after a single and repeated oral administration of ¹⁴C labeled Q-35[(±)-1-cyclopropyl-6-fluoro-1, 4 dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid], a new fluoroquinolone antimicrobial agent, was studied in rats.
1. The levels of the radioactivity in most tissues reached their maximum at 30 min after a single oral administration of ¹⁴C-Q-35 at the dose of 20 mg/kg. The peak levels of radioactivity in all tissues except, brain, eyeball and fat, were higher than those observed in plasma. The radioactivity distributed rapidly and well to many tissues, and there was a rapid elimination of radioactivity from these tissues.
2. In the tissues, to which a high degree of radioactivity distributed, the total radioactivity consisted mostly of unchanged Q-35 and of small quantities of metabolites. It was suggested that almost all Q-35 administered distributed to various tissues and was remaining as an unchanged form without metabolism.
3. During 14 days repeated administration, the tissue levels of radioactivity were nearly similar to those after first administration, and the excretion rates of radioactivity into the urine and feces were nearly constant.
Tissue levels of radioactivity after the 14th administration decreased rapidly in parallel with the plasma level. Neither an accumulation nor a residue of radioactivity was obserbed.

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Transfer of radioactivity into fetus and milk were studied after a single oral administration of ¹⁴C-Q-35 at the dose of 20 mg/kg in pregnant and in lactating rats.
1. Whole body autoradiography of pregnant rats showed that radioactivity distributed well and rapidly in the body, except brain and eye ball. At 24 h after administration, radioactivity in tissues was almost completely eliminated.
Distribution patterns of radioactivity in fetus were similar to those in mother. However, the radioactivity in fetus was relatively low.
2. The levels of radioactivity in milk were higher than those in plasma suggesting that Q-35 transfers into milk.

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The metabolism of ¹⁴C labeled Q-35 [(±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7 (3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid], a new fluoroquinolone antimicrobial agent, was studied in rats and dogs.
1. Two metabolites were identified in the urine and the bile (or the feces) after a sigle oral administration of ¹⁴C-Q-35 to rats and dogs: glucuronic acid conjugate of Q-35 as the main metabolite and aminopiperidinyl N-desmethylated derivative (N-desmetyl Q-35) as a minor metabolite.
2. Q-35 glucuronide was excreted mainly in the bile or feces. Most of the radioactivity in the urine and the plasma was unchanged Q-35.
3. The bioautographic study revealed that the antibacterial activity present in the urine and the bile was related to unchanged Q-35 but not to its metabolites. These results indicate that the transformation of Q-35 hardly occurs and that most of the drug administerd remains unchanged Q-35 in rats and dogs.

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The absorption, metabolism and excretion of CS-670 were studied in mice, rats and dogs after oral administration of ¹⁴C-labeled compound.
1. After oral dosing to mice at a dose of 10 mg/kg, total radioactivity in plasma reached the Cm., of 15.8μg/ml at 15 min and disappeared with T_1/2 of 0.41 hr up to 2 hr. The amount of the unchanged CS-670 in plasma was very low. The plasma major metabolite was cis-OH form.
2. Within 48 hr after dosing to mice, 77.3% and 14.1% were excreted in the urine and feces, respectively. The major metabolites found in urine were identified as glucuronides of cis- and trans-OH forms.
3. After oral administration to male rats at a dose of 2 mg/kg, plasma concentration of radioactivity reached the C_max of 1.70 μg/ml at 30 min and disappeared with T_1/2 of 1.47 hr up to 3 hr. The coressponding values of C_max, Tax and T_1/2 in female rats were 3.52μg/ml, 30 min and 2.81 hr, respectively. The unchanged CS-670 in plasma was only present in trace amount and trans-OH form was detected as a major metabolite of which levels were higher in plasma of female rats than male rats.
4. The urinary and fecal excretions of radioactivity were 72.5% and 20.7% of the dose, respectively, within 144 hr after oral dosing to male rats. In female rats, the radioactivity was excreted in urine at 76.7% of the dose and in feces at 17.6% of the dose. The urinary major metabolites were diol derivatives and their excretion in 24 hr urine was larger in male rats (92.8% of urinary radioactivity) than that (67.8%) in female rats.
5. The biliary excretion of radioactivity was 69.5% of the dose after oral administration to bileduct cannulated male rats, and 89.5% of radioactivity excreted in the bile was reabsorbed from the intestine. Glucuronide of trans-OH form was excreted in the bile as a major metabolite.
6. After administration to male dogs at a dose of 2 mg/kg, the plasma level of radioactivity reached a maximum of 4.87 μg/ml at 1 hr and disappeared with T_1/2 of 2.16 hr up to 6 hr. The corresponding values of Tmax, C_max, and T_1/2 in female dogs were 2 hr, 4.09μg/ml and 2.21 hr, respectively.
7. In male dogs, 57.9% and 38.9% of the dosed radioactivity were excreted within 120 hr in urine and feces, respectively. In female dogs, the urinary and fecal excretions of radioactivity were 60.6% and 32.3%, respectively. The urinary major metabolite was suggested to be amino acid conjugate of trans-OH form in both male and female dogs.
8. Marked species differences were observed in the metabolism of CS-670 between mice, rats and dogs. Namely, the double bound of CS-670 was rapidly reduced in all animals studied, then the carbonyl group was reduced to yield mainly traps-OH form in rats and dogs and cis-OH form in mice. These mono-ols were excreted in urine after being transformed to the diols in rats, probably an amino acid conjugate in dogs and a glucuronic acid conjugate in mice. Furthermore, sex differences were observed in the formation of diols in rats.

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The absorption, distribution and excretion of ¹⁴C-KW-4679 after oral or intravenous administration at a dose of 1 mg/kg were studied in male and female rats. Also the absorption and excretion of ¹⁴C-KW-4679 after oral administration at a dose of 25 mg/kg in male rats were studied.
1) ¹⁴C-KW-4679 was rapidly absorbed and the extent of absorption was estimated to be 91% or higher after oral administration of 1 mg/kg. The drug was presumably absorbed mainly in the region from the duodenum to the jejunum.
2) Plasma radioactivity reached C_max at 0.5 hr after oral administration of 1 mg/kg to fasting male rats and then disappeared biexponentially with terminal half-life of 16.8 hr. By 96 hr after administration, 42.6% and 53.5% of the administered radioactivity were excreted in urine and feces, respectively. In bile, 46.0% of radioactivity was excreted by 72 hr after administration. The excretion of radioactivity in urine, feces and bile almost completed within 24 hr after administration.
3) Delayed T_max and reduced C_max were observed after oral administration to non-fasting rats compared to fasting rats. There was no significant difference in AUC_0-∞. No difference was observed in the excretion of radioactivity in urine and feces, whether animals were fasted or not.
4) Larger AUC_0-∞ by about 18% was obtained after oral administration to female rats as compared with male rats. A tendency of lower fecal excretion and higher urinary excretion of radioactivity was demonstrated in female rats.
5) After intravenous administration of 1 mg/kg to fasting male rats, radioactivity was eliminated from plasma triexponentially with terminal half-life of 34.2 hr. By 96 hr after administration, 51.7% and 43.0%of the administered radioactivity were excreted in urine and feces, respectively.
6) Radioactivity was rapidly distributed to almost all tissues after oral administration of 1 mg/kg to fasting male rats. Except digestive organs, higher than in plasma levels of radioactivity were observed in the liver, kidney and urinary bladder. The lowest level of radioactivity was observed in the brain, where the level was about 1/25 of that in plasma, among all the organs examined. Radioactivity in tissues was eliminated almost in parallel with plasma concentration.
7) The radioactivity excreted in bile was reabsorbed (8.6%).
8) T_max, dose-normalized C_max and AUC_0-t of plasma radioactivity after oral administration at a dose of 25 mg/kg to fasting male rats was almost equal to that after oral administration at a dose of 1 mg/kg, respectively. Higher urinary excretion of radioactivity after 25 mg/kg dosing than that after 1 mg/kg dosing was observed.

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The disposition of ¹⁴C-KW-4679 after a single and repeated oral administration for 21 days to male rats at a dose of 1 mg/kg and the effect of repeated oral administration of KW-4679 to female rats for 7 days on drug metabolizing enzyme system, were studied.
1) Plasma levels of radioactivity collected at 24 hr after 1st, 7th, 14th and 21st dose was 7.8, 10.8, 13.3 and 12.1 ng eq./ml, respectively and nearly reached the steady state during 7th to 14th dose. The level of radioactivity at 24 hr after the last administration was 1.2 times higher than that after the initial administration. But the C_max and AUC_0-24 of plasma level of radio activity after the last administration were similar to those after the initial administration. The tissue level of radioactivity, which was measured at 24 hr after the 1st, 7th, 14th and 21st dose, reached the steady state during 7th to 14th dose as observed with blood and plasma levels of radioactivity. After the last administration, the level of radioactivity in fat decreased more slowly compared to that after a single dose.
2) The radioactivity excreted into urine and feces was measured every 24 hr after daily administration. The excretion was kept constant after the 8th dose. The cumulative excretion until 168 hr after 21th dose were 36.5% in urine and 57.2% in feces, respectively. This ratio was kept virtually constant from the initial to the final administration.
3) Repeated oral administrations of 0.1 to 25 mg/kg of KW-4679 to female rats for 7 days did not affect drug metabolizing enzyme system of the liver microsomes.

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The absorption and excretion of ¹⁴C-KW-4679 after oral administration were studied in dogs.
1) The plasma level of radioactivity reached the peak (723.2 ng eq./ml) at 1.13 hr after administration, and then radioactivity was eliminated almost monophasically with a half-life of 4.53 hr.
2) The transfer of ¹⁴C-KW-4679 to blood cells was nearly constant in the period from 2 to 12 hr after administration with an extent of 31.7 to 35.5%.
3) The serum protein binding of ¹⁴C-KW-4679 in vivo was nearly constant (53.1 to 56.8%) from 0.5 to 12 hr after administration.
4) By 168 hr after administration, 73.4% and 22.9% of the dose were excreted in urine and feces, respectively, with a total excretion of 96.3%. The excretion had been almost completed within 48 hr after administration.

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The metabolism of KW-4679 was investigated in rats and dogs after oral administration of ¹⁴C-KW-4679 or KW-4679.
1) After oral administration to rats, N-mono-demethyl-KW-4679 (Ml), N-di-demethyl-KW-4679 (M2), KW-4679 N-oxide (M3), C8-hydroxyl-KW-4679 (M5), M5 sulfate (M4) and oxidated M5 (M6) were identified as the metabolites of KW-4679 in bile in addition to unchanged KW-4679.
2) When ¹⁴C-KW-4679 was orally administered to fasting male rats, 66.4% of radioactivity detected in plasma at 0.5 hr after administration, accounted for the unchanged KW-4679. The main metabolite in plasma was M1 (7.7%). In urine, also, radioactivity was present mainly as the unchanged KW-4679, which represented 27.3% of dose. The main metabolite excreted in urine was M1 (6.0%) followed by M6, M5, M2, M3 and then by M4. The main metabolite in bile was M6 followed by M4 and then by the unchanged KW-4679. In feces, 19.4% of administered radioactivity was excreted as the unchanged KW-4679. The main metabolite in feces was M5 (5.1%) followed by M6, M1, M4, M2 and then by M3.
3) After oral administration to fasting female rats, the unchanged KW-4679 was a main component of radioactivity excreted in urine, same as in male rats.
4) When ¹⁴C-KW-4679 was orally administered to fasting male dogs, 71.1% of radioactivity detected in plasma at 0.5 hr after administration was the unchanged KW-4679. The main metabolite in plasma was M3 (11.0%). The major component in urine was the unchanged KW-4679 (51.6%) followed by M1 (4.5%), M3, M5, M2, M6 and then by M4. KW-4679 was the major component excreted also in feces, representing 6.0% of dose followed by M5, Ml, M6, M4 and then by M2.
5) The metabolic pathway of KW-4679 in rats and dogs consisted of oxidative N-demethylation of the side chain and hydroxylation of dibenzoxepine ring and its sulfation and further oxidation of N-atom in the side chain.

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The transfer of ¹⁴C-KW-4679 to fetus and milk after oral administration at a dose of 1 mg/kg to rats was investigated.
1) The plasma level of radioactivity rapidly increased after oral administration of ¹⁴C-KW-4679 to 12th and 19th-day pregnant rats. Radioactivity was then eliminated from plasma almost biexponentially.
2) The level of radioactivity in fetus after oral administration to 12th-day pregnant rats was lower than that in maternal plasma, the ratio was as low as 0.18. In dams, level of radioactivity higher than that in the plasma was observed in the kidney and liver.
3) The level of radioactivity in fetal plasma and tissues was 0.07 to 0.38 times that in maternal plasma after oral administration to 19th-day pregnant rats. The fetal tissue level of radioactivity decreased virtually in parallel with the level in maternal plasma.
4) When ¹⁴C-KW-4679 was administered to lactating rats, the level of radioactivity in the milk showed the delayed peak as compared to that in the plasma. The level of radioactivity in the milk was always higher than that in the plasma from 4 hr after administration, and the radioactivity was eliminated from the milk more slowly than from the plasma. The AUC of radioactivity in the milk was about 1.5 times larger than that in the plasma. The radioactivity in the suckling rats reached the peak level at 24 hr after administration, decreasing nearly in parallel with radioactivity in the milk afterward. When ¹⁴C-KW-4679 was orally administered to 3-weeks rats, a higher C_max but almost similar elimination of radioactivity was observed as compared with matured rats.
5) When 1 mg/kg of the unlabeled KW-4679 was orally administered to lactating rats, the milk to plasma concentration ratio of unchanged KW-4679 rose from 0.36 to 1.97 during 0.25 to 24 hr after administration. The AUC_0-24 of unchanged KW-4679 in the milk and plasma were 66.3% and 74.5% of AUC_0-24 of radioactivity in the milk and plasma, respectively.

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The disposition of new antiallergic (Z)-11-[(3-Dimethylamino) propylidene]-6, 11-dihydro-dibenz[b, e]oxepin-2-acetic acid hydrochloride (KW-4679) was studied in rats, guinea pigs, dogs and monkeys using highly sensitive RIA method.
1) Cross-reactivities of mono-demethly-KW-4679 (M1) and di-demehtyl-KW-4679 (M2), both of which were metabolites of KW-4679 in rat and dog plasma, were 27 and 4%, respectively. Plasma concentrations measured by RIA method were well correlated with the those by HPLC-RIA method. This RIA method provided good reproducibility ranging from 0.1 to 2 ng/ml with lower limit of quantification of 0.1 ng/ml.
2) KW-4679 disappeared from plasma after intravenous administration triphasically. Total clearance of KW-4679 in rats was comparable to that in guinea pigs with 1.31 to 1.45 1/hr/kg, which was greater than those in dogs (0.32 1/hr/kg) and monkeys (0.73 1/hr/kg). The urinary excretion of KW-4679 was 43.1, 62.1 and 50.1% in rats, dogs and monkeys, respectively. Not only glomerular filtration but also tubular secretion were likely to be involved in urinary excretion of KW-4679 in rats and monkeys.
3) After oral administration to rats, guinea pigs and dogs, KW-4679 was rapidly absorbed. Bioavailabilities were between 60.8 and 83.3%. The elimination half-life was generally constant with 5.8 to 10.6 hr in these animal species. The disposition of KW-4679 was linear in the dose range studied. Absorption of KW-4679 in monkeys was slightly slower than other animals, but bioavailability was almost 100%.
4) The unbound fractions of KW-4679 in animal sera ranged 37 to 50% in vitro. Also, this was dose-independent in the range from 0.1 to 1000 ng/ml.
5) Total and renal clearances of KW-4679 were in good allometric relation with body weight of respective animal species.

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