The pharmacokinetics, distribution, and excretion of radioactivity and the main metabolites, M-1, M-2 and M-3, were studied in male rat after a single intravenous administration of ¹⁴C-labeled roxatidine acetate hydrochloride (TZU) at a dose of 10 mg/kg. The concentrations of these three metabolites in plasma, tissues and urine were simultaneously quantified with LC/MS-SIM using corresponding deuterium-labeled compounds as internal standards.
1) The total radioactivity in the blood decreased with the half-lives of 0.38 and 3.82 hr in α-phase and β-phase, respectively. The plasma concentration of M-1, the active metabolite, decreased with the half-lives of 0.17 hr in α-phase and 0.77 hr in β-phase.
2) At 15 min after administration, a high radioactivity was found in the liver, kidney, stomach, small intestine, parotid and submaxillary glands. At 72 hr after administration, the radioactivity was less than 0.1% of the dose or below the detection limit in any tissues.
3) The metabolites in tissues were qualitatively analyzed by radio-HPLC. The radioactivity of the M-1 fraction was the highest in the brain, stomach, small intestine and kidney, then followed by that of the M-2 and M-3, the total radioactivity mainly consisted of those three fractions.
4) The concentrations of three metabolites were quantified with LC/MS-SIM in the brain, lung, stomach, small intestine, liver, kidney and testis. All these metabolites disappeared rapidly, the half-lives were below 3.4 hr, in every tissue except for the testis. Although the radioactivity in the testis slowly decreased with the half-life of 10.5 hr, it accounted for M-2 and M-3, because they disappeared similarly to the radioactivity.
5) In the target organs, stomach and small intestine, the concentration of M-1 was the highest, confirming that TZU has an advantage as an H₂-receptor antagonist.
6) Only in the liver, the level of the phenolic metabolite, M-3, was the highest of the three metabolites. This finding indicated that the metabolite might be mainly produced through oxidative dealkylation in liver.
7) Approximately 87 and 8 % of the dosed radioactivity were excreted within 48 hr after administration in the urine and feces, respectively. The main metabolite in the urine was M-3, consisting of 29% of the dose, and about half of that was in the conjugated form. In feces, the excretion ratios of these three metabolites were almost equal, 0.3% of the dose.
8) About 20% of the dosed radioactivity was excreted into bile in billiary fistular rats. The radioactivities in the M-1 and M-2 fractions were each 0.3% of the dose. The M-3 fraction comprised about 8%, almost all of which was in the conjugated form.

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Blood and plasma concentrations, metabolism and excretion were investigated in male dogs after a single intravenous administration of [¹⁴C] TZU.
1. Blood concentration of radioactivity decreased gradually until 2 hr after dosing, and then declined rapidly until 12 hr, followed by the decrease with halflife of 7.34 hr. The time-profile of radioactivity in the plasma was similar to that of the blood.
2. Three metabolites, M-1, M-2 and M-3 were simultaneously determined by LC/MS-SIM in dog plasma and urine.
3. Plasma concentration of M-1 reached the C_max of 15.0 nmol/ml at 10 min after dosing and declined biphasically with half-lives of 0.22 hr (T_1/2α) and 1.71 hr (T_1/2β). Finally it decreased below the detection limit at 24 hr. M-2 reached the C_max of 2.8 nmol/ml at 2 hr and declined biphasically with respective halflives of 1.93 hr (T_1/2α) and 6.77 hr (T_1/2β). M-3 reached the C_max of 0.5 nmol/ml at 2 hr and declined with half-life of 3.05 hr.
4. The excretions of radioactivity in urine and feces were 71.9% and 15.1% of dose within 24 hr after administration, respectively. 98.4% of administered radioactivity was excreted in urine and feces within 168 hr.
5. The amount of M-3 in the urine after hydrolysis with β-glucuronidase and arylsulfatase was 4 times higher than that before hydrolysis. It indicated that M-3 was almost excreted into urine as glucuronide and/or sulfate. On the other hand, M-1 and M-2 were excreted in urine in unconjugated form.
6. 50% and 60% of radioactivity in dog plasma and urine were composed of three metabolites (M-1, M-2 and M-3) determined by LC/MS-SIM.

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Pharmacokinetics of the two enantiomers [FV(+); 3R, 5S-isomer, FV(-); 3S, 5R-isomer] of Fluvastatin (FV) were investigated in rats after single administration of [¹⁴C]FV or ¹⁴C-labeled enantiomers.
1. After intravenous administration of [¹⁴C]FV (5mg/kg), the total body clearance (CL_tot) for FV(+) was about 2 times higher than that for FV(-) . The volume of distribution at steady state (Vd_ss) for FV(-) was 2.5 times higher than that for FV(+) . After oral administration (5 mg/kg), C_max and t_max values were not different between enantiomers. The values of half-life (t_1/2) and AUC for FV(-) were 2 ?? 5 times higher than those for FV(+).
2. Pharmacokinetic(PK) parameters (CL_tot, Vd_ss etc.) of radioactivity after intravenous administration of [¹⁴C]FV(+) or [¹⁴C]FV(-) (2.5 mg/kg) were significantly different between enantiomers. The value of t_1/2 for FV(-) was significantly longer than that for FV (+) .
3. The absorption rates and the bioavailabilities of enantiomers did not differ.
4. The tissue distribution of radioactivity after intravenous administration of [¹⁴C]FV(+) or [¹⁴C]FV(-) was different from each other at 0.5 hr and 24 hr.
5. No stereoselectivity was observed in the serum protein binding.
6. No stereoselective biliary excretion of unchanged enantiomers was observed. However, the biliary excretion rate of radioactivity after intravenous administration of [¹⁴C]FV(+) was faster than that of [¹⁴C]FV(-).
7. β-oxidized metabolite, M-7, was detected in both plasma and bile only after administration of [¹⁴C]FV(+). Some unknown metabolites (UK1 ?? UK4) were observed in the bile, and UK4 was only detected after administration of [¹⁴C]FV(+).
From these results, the difference in the PK profiles of enantiomers after administration of FV seems to be caused by the change in the biliary excretion rates of metabolites following the stereoselective metabolism.

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Pharmacokinetic and pharmacodynamic (PK/PD) analyses for a novel thromboxane synthetase inhibitor, DP-1904, were performed to predict its PK/PD profiles in human after single and repeated oral administration. The pharmacodynamics of DP-1904 was characterized by serum levels of thromboxane B₂(TXB₂), a pharmacological marker for thromboxane synthetase inhibition. Based on a quantitative relationship between the plasma DP-1904 and serum TXB₂ concentrations after single oral dosage, IC₅₀ and E_max values were estimated to be 0.54 ng/ml and 94%, respectively. An integrated, simple PK/PD model was developed to simulate the changes in serum TXB₂ levels after single oral administration of DP-1904 at various doses, and the simulation curves corresponded well with the observed data. The PK/PD model was then used to predict a pharmacological profile of DP-1904 after repeated oral doses in human; the predicted curves were in relatively good agreement with the observed data. Thus, it is suggested that our PK/PD model is feasible and practical for developing optimum dosing regimens of DP-1904 in clinical situations.

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The absorption, distribution and excretion of radioactivity were investigated after a single oral administration of 1 mg/kg of ¹⁴C-ramosetron hydrochloride to rats.
1. Blood radioactivity levels reached the C_max at 15 min after administration, and then decreased bi-phasically with a terminal half life (t_1/2) of 2.1 hr. Plasma radioactivity levels showed 1.2-1.5 fold higher values than that of blood. Plasma unchanged drug levels reached the C_max at 15 min after dosing, and then decreased with a t_1/2 of 0.85 hr. The ratios of the unchanged drug to total radioactivity level in the plasma were 1.4-9.9%.
2. The absorption ratios of ¹⁴C-ramosetron hydrochloride were highest in the duodenum, followed by the jejunum, ileum and colon, and lowest in the stomach.
3. Radioactivity distributed quickly into various tissues, showing a peak level at 30 min after dosing in most tissues. Radioactivity levels were highest in the liver, followed by the small intestine, kidney, stomach, large intestine and lung, and lowest in the brain. Radioactivity disappeared rapidly from the tissues, and the levels in most tissues at 24 hr after dosing were less than 2% of the peak levels.
4. Within 72 hr after dosing, 23.1% and 75.0% of the dosed radioactivity was excreted in the urine and feces, respectively. In bile-duct cannulated rats, 71.1% and 26.3% of the dosed radioactivity was excreted within 72 hr in bile and urine, respectively.

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The tissue distribution and excretion of ¹²⁵I-iodixanol have been studied in the rat following single intravenous administration of 600 mg/kg.
Following single intravenous dose of ¹²⁵I-iodixanol, the mean C_max concentration of radioactivity in plasma was measured at 5 min, during the first sampling, and was 1079 μg equiv. I/ml. Mean concentrations then declined rapidly to 97.3 μg equiv. I/ml at 1 hr and to 14.3 μg equiv. I/ml at 2 hrs; at later times, concentrations were below the limit of accurate determination. There was no notable specific uptake of radioactivity into blood cells.
Following intravenous dosing, the radioactivity was rapidly and mainly excreted in the urine. During 72 hrs after dosing, the urinary excretion accounted in average for 88.3% of the dose and fecal excretion accounted for 5.9% of the dose. The total recovery of radioactivity during 72 hrs was 95.3% of the administered dose.
The highest levels of radioactivity occured at 0.5 hr and 1 hr in most tissues. At 0.5 hr, the following concentrations (expressed as μg equiv. I/g or ml) were found in kidneys (672), plasma (331), aorta (295), vena cava (246), thyroid (223) and whole-blood (202). After 2 hrs, concentrations generally declined, and by 72 hrs concentrations were near to, or below, the limit of accurate measurement, in most tissues. At 72 hrs, notable concentrations were only detected in the thyroid and kidney.
The extent of plasma protein binding of radioactivity was minimal and ranged between 1 % and 10% of the plasma radioactivity during 2 hrs after dosing.
In conclusion, this study has shown that after intravenous administration of ¹²⁵I-iodixanol to rats, the drug is rapidly and generally distributed in the tissues. Radioacivity is generally rapidly cleared from most tissues and from plasma and is very rapidly excreted, almost exclusively in the urine.

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The feto-placental transfer of ⁵⁹Fe-sodium ferrous citrate (⁵⁹Fe-SCF) and ⁵⁹Fe-ferrous sulfate (⁵⁹FeSO₄)were studied in pregnant rats on day 18 of gestation after a single oral administration of ⁵⁹Fe-SCF (0.75 mg/kg) and ⁵⁹FeSO₄ (1.5 mg/kg). The blood levels of radioactivity at 6 h after administration of ⁵⁹Fe-SCF was higher than that of ⁵⁹FeSO₄, and even at 24 h, the blood levels of radioactivity after administration of ⁵⁹Fe-SCF was about 3.4-fold higher than that of ⁵⁹FeSO₄. The plasma levels of radioactivity rapidly decreased in monoexponential manner untill 24 h, when ⁵⁹FeSO₄ was orally administered. In the case of ⁵⁹Fe-SCF, the plasma levels of radioactivity reached maximum at 6 h and rapidly decreased thereafter.
The highest radioactivity of ⁵⁹Fe-SCF in the maternal tissues was found in the spleen, followed by the bone (including bone marrow) and liver. There was almost no distribution of radioactivity in the brain, brown fat and muscle, after oral administration either ⁵⁹Fe-SCF or ⁵⁹FeSO₄. The radioactivity in the placenta, fetues and amnitoic fluid were higher than in the maternal blood for the both compounds, however, the radioactivity in the placenta, fetues and amniotic fluid after ⁵⁹Fe-SCF administration were higher than those of ⁵⁹FeSO₄. This finding indicates that SCF in comparison to FeSO₄, has great efficacy for intestinal absorption in pregnant rats and bio-utilization of iron for fetues.

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Blood levels of tacrolimus (FK506) determined by three different methods, were compared after intravenous (i.v.) and oral administration of ¹⁴C-FK506 to rats. The methods used were high performance liquid chromatography-mass spectrometry (LC/MS) with electrospray ionization mode, enzyme immunoassay (EIA) using anti-FK506 monoclonal antibody, and the counting of radioactivity. Also, the composition of the radioactivity in the whole blood and plasma of rats after i.v. and oral administration was analyzed by the high performance liquid chromatography (HPLC).
1. FK506 concentrations determined by EIA were almost equal to those determined by LC/MS in the whole blood and plasma of rats after ix. injection. The ratio of FK506 levels measured by EIA to those by LC/MS ranged from 1.1 to 1.3 and from 1.4 to 2.0 in the whole blood and plasma, respectively, after oral administration.
2. Levels of radioactivity in all blood samples were higher than those determined by LC/MS and EIA. The ratio of the concentrations of the unchanged FK506 to total radioactivity decreased gradually after administration of FK506 and the respective values at 0.25 and 8 hours after dosing were 0.8 and 0.6 in the whole blood and 0.7 and 0.2 in the plasma after i.v. injection, and 0.4 and 0.1 in the whole blood and 0.08 and 0.04 in the plasma after oral administration.
3. At 0.5 and 8 hours after i.v. injection, the unchanged FK 506 in the whole blood and plasma accounted for more than 84 and 59%, respectively, of total radioactivity eluted on HPLC. After oral administration, the unchanged FK506 accounted for 62% in the whole blood and 35% in the plasma at 0.25 hour. The metabolite, 13-0-mono-desmethyl FK506 was detected in all blood samples, and ranged from 2 to 8 % of the eluted radioactivity in the whole blood and from 3 to 20% of that in the plasma.
4. The results indicate that FK506 levels measured by EIA reflect the levels of the unchanged FK506 in the whole blood and plasma after i.v. injection of FK506 to rats and those in the whole blood after oral administration, and part of metabolites in the blood increase with time after administration.

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