The absorption, distribution, metabolism and excretion of [¹⁴C]dorzolamide hydrochloride (MK-507) were studied in rats after single administration. In vitro plasma protein binding was also investigated.
1. Following intravenous administration of [¹⁴C]dorzolamide hydrochloride to male rats at doses ranging from 0.1 to 5 mg/kg, blood AUC values increased proportionally with doses up to 0.5 mg/kg, but no increase in the values was observed for the dose range of 1 to 5 mg/kg. Most of the radioactivity in blood was present in erythrocytes. The elimination of radioactivity from the blood was very slow and the estimated t_1/2 was 10.5-11.3 days.
2. No sex differences were observed in blood concentration profiles regardless route of administration, oral or intravenous. After oral administration, almost all [¹⁴C]dorzolamide was absorbed.
3. After intravenous administration at the dose of 0.5 mg/kg, most of the radioactivity was distributed in blood. At 30 min after dosing, the highest radioactivity was found in the kidney, followed by lung, spleen, bone marrow, stomach, liver, caecum and large intestine. The concentration-time profiles of most tissues were similar to that of blood.
4. Within 31 days after intravenous administration at the dose of 0.5 mg/kg, the excretion of radioactivity accounted for 74.7% in urine and 11.8% in feces. Within 24 hr after oral administration at the dose of 0.5 and 5 mg/kg, 24.7 and 73.8% of administered radioactivity were excreted in urine, respectively.
5. N-deethylated dorzolamide was found in the blood, urine and tissues. The ratio of the radioactive N-deethylated metabolite to the total radioactivity in blood or in tissues after administration at the dose of 5 mg/kg was larger than those after dosing at the dose of 0.5 mg/kg.
6. The in vitro binding of dorzolamide and N-deethylated dorzolamide to plasma proteins accounted for less than 30% in all species studied, and these compounds were mainly bound to albumin.

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Dorzolamide hydrochloride (MK-507), (-)-(4S, 6S)-4-ethylamino-5, 6-dihydro-6-methyl-4H-thieno-[2, 3-b]-thiopyran-2-sulfonamide-7, 7-dioxide monohydrochloride, is a new topical carbonic anhydrase inhibitor. The binding of dorzolamide and its N-deethylated metabolite (L-706, 803) to rat erythrocytes was investigated, and the pharmacokinetics of dorzolamide in rats was studied after a single intravenous administration.
1. Dorzolamide was incorporated into rat erythrocytes rapidly, while the uptake of L-706, 803 was slower.
2. There were two types of binding site for dorzolamide and L-706, 803 in rat erythrocytes. For both dorzolamide and L-706, 803, the maximum binding capacity was about 60 μM for the high affinity isozyme and 30 μM for the low affinity isozyme.
3. The Kd values of dorzolamide and L-706, 803 for low affinity binding were 0.387 and 0.497 μM, respectively. The Kd values of dorzolamide and L-706, 803 for high affinity binding were about 1/100 and 1/250 of those for low affinity binding, respectively.
4. After administration of dorzolamide hydrochloride to rats at the dose of 0.5 mg/kg, dorzolamide and L-706, 803 were not detected in plasma. At the dose of 5 mg/kg, the plasma half-lives of dorzolamide and L-706, 803 were 1.0 and 2.6 hr, respectively.
5. At the dose of 0.5 mg/kg, the half-lives of dorzolamide and L-706, 803 in blood were 157 and 116 hr, respectively, and decreased to respective values of 101 and 99 hr after administration of 5 mg/kg.
6. After administration of dorzolamide hydrochloride at the dose of 0.5 mg/ kg, the blood AUC values of dorzolamide and L-706, 803 were 1093 and 115 μg hr/ml, respectively. The AUC value of dorzolamide at the dose of 5 mg/kg decreased by 50% and that of L-706, 803 increased about five-fold.
7. The Vd_ss and CL_tot of dorzolamide were 99.9 ml/kg and 0.46 ml/hr/kg after administration of 0.5 mg/kg and increased 15 and 25-fold after 5 mg/kg, respectively.

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The urinary metabolites in the unconjugated fraction, obtained from dogs orally given Pirmenol, were investigated by gas chromatography/mass spectrometry (GC/MS). Six metabolites, namely two epimeric monohydroxydimethylpiperidines (M1-1: trans 4-OH and M1-2: cis 4-OH), dimethyldehydropiperidine (M2), phenol (M3) and guaiacol (M5), and amine (M9) together with unchanged Pirmenol were unequivocally characterized by mass spectrometry as compared with the authentic samples.
In addition, three metabolites were separated from the conjugated fraction. Their structures were confirmed by a naphthoresorcinol color test on thin-layer chromatogram and liquid chromatography/mass spectrometry (LC/MS), and GC/MS after treatment with β-glucuronidase. These conjugated metabolites were proved to be glucuronides of M1-1, M3 and M5.

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The metabolic fate of Pirmenol and its sex-related biotransformation have been studied in rats.
Initially, the urinary metabolites were examined by comparing retention times of radioactive peaks with those of reference compounds in high-performance liquid chromatography (HPLC) following oral administration of ¹⁴C-Pirmenol. Three main metabolites as M3G, M4G and M5G accompanied with a few minor metabolites were identified. The major metabolites were unequivocally characterized on the basis of mass spectral data after separation from urine of rats administered unlabeled Pirmenol.
When ¹⁴C-Pirmenol was given to rats, plasma levels of radioactivity were slightly higher in female than in male rats, although the plasma level profiles were similar. Urinary and biliary excretion rates of radioactivity for 24 hr were somewhat higher in female (25 and 83 %) than in male rats (14 and 77%). Therefore, radioactivity was principally excreted in bile and excretion patterns were similar in male and female rats.
The metabolites in plasma, urine and bile were determined by HPLC. Main metabolites, M3G, M4G and M5G, corresponded to 45-90% of total radioactivity in each sample. A certain sex-related difference was observed in the levels of major metabolites. In male rats, the M5G was predominant, while in female M3G and M5G were major metabolites occurring in equal quantities. These results suggest that major metabolic pathway of Pirmenol in rats is hydroxylation of the aromatic ring and subsequent catechol O-methylation and/or glucuronidation.

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Pharmacokinetics of large molecules, such as rG-CSF and erythropoietin after subcutaneous administration, was discussed based mainly upon the observations of kinetics of rG-CSF and other molecules. The mean absorption time (MAT) and the variance of absorption time (VAT) of rG-CSF were calculated, and the ratio of VAT/(MAT)² was less than 1, suggesting that the absorption process might be catenary process. The absorption processes of large molecules might consist of molecule independent and dependent processes. The kinetics of erythropoietin suggested that the injection volume might contribute to the molecule independent process.

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The absorption, tissue distribution and excretion of [¹⁴C]-finasteride were studied in male rats after repeated oral administration for 22 days at a dose of 5 mg/ kg/day. The effects of finasteride on the drug metabolizing enzyme system in male rats after repeated oral administration for 7 days were also investigated.
1. A slight decrease in T_max and increase in C_max of the plasma radioactivity were observed after the final administration of [¹⁴C]-finasteride, as compared to those after the first administration. Furthermore, t_1/2 and AUC values of the last dose were similar to those after the first dose, suggesting that both absorption and excretion rates do not change during the repeated administration.
2. No change in the daily excretion of radioactivity in urine and feces was observed during the repeated dosing. Within 96 hr after the last dosing, urinary and fecal excretion of radioactivity were 1.7% and 88.5% of the administered dose, respectively, indicating that the main excretion route is fecal excretion.
3. The levels of radioactivity were higher in all tissues at 24 hr after the last dosing than after the first dosing, particularly in fat pad which contained 61 times higher concentration. Although the radioactivity was generally eliminated slower from the tissues after the last dosing than from the plasma, no significant amount of radioactivity was accumulated in the tissues.
4. Repeated oral administration of finasteride at doses of 5 and 80 mg/kg/day for 7 days did not have any effect on liver weight, microsomal protein concentration and drug metabolizing enzyme system, except that a moderate and significant increase in aniline p-hydroxylase activity was observed for the high dose group. However, this activity returned to the basal level at 1 week after the last administration.

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Absorption, metabolism and excretion of lactitol were studied in rats and dogs after intravenous or oral administration of ¹⁴C-lactitol.
1. After intravenous administration, almost all the radioactivity in plasma was due to the unchanged form. ¹⁴C-Lactitol was eliminated from plasma with half-lives of 0.352 hr in rats and 0.594 hr in dogs.
2. After oral administration, the plasma levels of radioactivity reached maximum level 6.0 hr in rats and 9.3 hr in dogs, then decreased slowly. Most of the radioactivity was due to metabolites of ¹⁴C-lactitol, and the unchanged form was hardly detected in plasma. Systemic availabilities, based on plasma concentration of ¹⁴C-lactitol, were 1.69% in rats and 2.72% in dogs.
3. After oral administration to rats, plasma levels of radioactivity increased proportionally to administered dose (10 ?? 1000 mg/kg). There were no clear differences in plasma radioactivity between male and female rats.
4. After oral administration to rats, most of radioactivity was present as the unchanged form in the small intestine, but as metabolites such as sorbitol and volatile substances (probably short chain fatty acids) in the cecum. Therefore, it is suggested that lactitol is greatly metabolized in rat cecum by intestinal microflora.
5. After intravenous administration to rats and dogs, most of the administered radioactivity was excreted in urine as the unchanged form. After oral administration to rats, the excretion of radioactivity within 168 hr was 5.1, 16.1 and 65.0% of dose into urine, feces and expired air, respectively.
6. The protein binding of lactitol in vitro was investigated in rat, dog and human serum, but it was not bound to serum protein at the concentration range of 0.5 to 50 μg/ml.

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Distribution, transfer to fetus and milk were studied after single oral administration of 14C-lactitol to rats. Further, the absorption, metabolism, distribution, excretion and the effect on hepatic drug-metabolizing enzyme activities were also studied after repeated oral administration of 14C-lactitol or unlabeled lactitol to rats.
1. After single oral administration to male rats, the radioactivity was extensively distributed to the tissues except the central nervous system, eyeball, fat, skeletal muscle, aorta and testis. The radioactivity levels in the tissues reached the maximum level 10 hr after dosing and decreased slowly. There were no clear differences in the tissue distribution of radioactivity between male and female rats.
2. In pregnant rats, the radioactivity was higher in the fetus than in the maternal blood.
3. In lactating rats, the radioactivity was higher in the milk than in the plasma.
4. During 21-day consecutive oral administrations, the radioactivity in tissues accumulated gradually. After the 21st dose the radioactivity was eliminated from tissues more slowly than after the 1st dose.
5. The residual radioactivity present in tissues after single or repeated oral administration was considered to be that incorporated into tissue components, such as proteins and lipids.
6. The repeated oral administration of lactitol had no effect on the hepatic drug-metabolizing enzyme activities.

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Distribution and excretion of radioactivity were studied in male rats and male dogs after an intravenous dosing of ¹⁴C-FK037 (20 mg/kg).
1. After dosing to rats, plasma and blood levels of radioactivity declined rapidly; the radioactivities at 4 hr after dosing were less than 1% of the concentration at 5 min. The unchanged FK037 in the plasma disappeared two-exponentially with the terminal half-life of 0.43 hr. The ratio of the unchanged FK037 to total radioactivity in the plasma was more than 95% between 5 and 30 min after dosing, and then decreased gradually. The highest levels of radioactivity at 5 min after dosing were detected in the kidney, followed by plasma > blood > lung > liver, heart, spleen> brain. The radioactivities in the tissues, except for the kidney, were not detectable at 24 hr after dosing, and that in the kidney decreased to less than 0.5% of the maximum values. Urinary and fecal excretion of radioactivity was 92.6 and 4.6%, respectively, during 72 hr after dosing. Urinary and biliary excretion of radioactivity in the bile duct-cannulated rats was 98.6 and 1.8 %, respectively within 48 hr after administration. Urinary excretion of the unchanged FK037 was 95.4% during 48 hr, indicating that most of radioactivity in the urine was in the unchanged form.
2. After dosing to dogs, plasma and blood levels of radioactivity declined rapidly; the radioactivities at 8 hr after dosing were about 1 % of the concentration at 5 min. The unchanged FK037 in the plasma disappeared two-exponentially with the terminal half-life of 1.23 hr. The ratio of the unchanged FK037 to total radioactivity in the plasma was more than 97% between 5 min and 2 hr after dosing, and then decreased gradually. Urinary and fecal excretion of radioactivity was 99.8 and 2.4%, respectively, during 168 hr after dosing. Urinary excetion of the unchanged FK037 was 87.7% during 168 hr, indicating that most of radioactivity in the urine was the unchanged FK037.

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The ¹⁴C-labelled compound of FK037 (¹⁴C-FK037), a new antibiotics, was intravenously administered in male rats at a dose of 20 mg/kg once a day for 14 days, and its distribution, metabolism and excretion were investigated.
1. The radioactivity in the blood collected at 8 hr after 1st, 2nd, 10th and 14th dosing was as follows n.d. (not detected), 0.24, 0.42 and 0.43 μg eq./ml, respectively and attained the steady state after the 10th dosing. The area under the blood concentration-time curves up to infinite (AUC_0-∞, 22.6μg eq.·hr/ml) after single intravenous administration was similar to AUC_0-24hr after 7th and 14th dosing (19.2 and 24.4μg eq.·hr/ml, respectively).
2. Tissue levels of radioactivity in most of tissues at 8 hr after each dosing increased according to the multiple intravenous dosing for 14 days. The radioactivity in the tissues such as kidney, skin, bladder, stomach, lung, brown fat, skeletal muscle, prostate gland and parotid gland at 8 hr after the final dosing was 3.1-5.5 times higher than those at 8 hr after the 1st dosing. The radioactivity in other tissues at 8 hr after the final dosing was 2 times higher than those at 8 hr after the 1st dosing. Tissue concentration of radioactivity at 24 hr after the final dosing was less than 4% of those at 5 min after the final dosing.
3. During the multiple intravenous dosing of ¹⁴C-FK037, the ratios of unchanged FK037 and metabolites in plasma and urine were not changed. The most of radioactivity in plasma and urine consisted of the unchanged FK037.
4. During the multiple intravenous dosing of ¹⁴C-FK037, the ratios of urinary and fecal excretion of radioactivity were not changed. The urinary excretion of radioactivity was 94.2 and 94.3% of cumulative doses at 24 and 120 hr after the final dosing, respectively.

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The ¹⁴C-labelled compound of FK037, a new antibiotics, was administered intravenously at a dose of 20 mg/kg to pregnant and lactating rats to study its transfer into the fetus and milk, respectively.
1. The radioactivity levels in the fetus was only 1% of that in the maternal plasma at 5 min after intravenous dosing to rats on day 13 of gestation and was not detected at 24 hr after dosing. The radioactivity in the fetus was less than 1% of that in the maternal plasma at 5 min after intravenous dosing to rats on day 18 of gestation and declined to 19% of the maximum concentration at 24 hr after dosing. The whole body autoradiograms showed no radioactivity in the fetus after intravenous dosing to rats on day 13 and 18 of gestation.
2. The radioactivity in milk attained the maximum concentration of 0.93μg eq./ml at one hour after intravenous dosing to lactating rats, then declined with a half life of 5.6 hr until 8 hr after dosing, and was not detected at 24 hr after dosing.

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