The metabolic fate of ⁵⁹Fe-sodium ferrous citrate (SCF) and ⁵⁹Fe-ferrous sulfate were studied in rats. The rates of intestinal absorption and utilization of ⁵⁹Fe-SCF were compared with those of ferrous sulfate after oral administration.
The radioactivity was found in blood, 1 hr after oral administration of both compounds, indicating the rapid absorption from the gastrointestinal tract. Following either oral or intravenous administration, the radioactivity disappeared from plasma, and increased with time in the red blood cells suggesting the incorporation of ⁵⁹Fe into the hemoglobin. A high concentration of radioactiviy was observed in the liver and spleen, which accumulated nonhemin iron, but only small concentration of radioactivity was found in the brain and muscle, following either oral or intravenous administration.
The radioactivity was almost excreted via feces, although detectable quantities of radioactivity were excreted with urine after oral administration. The radioactivity excreted in feces was related to that which was not absorbed because it was not excreted to bile after either oral administration, or to feces after intravenous administration.
The radioactivty in blood and tissues after oral administration of ⁵⁹Fe-SCF was significantly higher than those observed after oral administration of ferrous sulfate. The fecal excretion of radioactvity after oral administration of ⁵⁹Fe-SCF was significantly lower than that after administration of ferrous sulfate. Thus, this finding indicates that SCF in comparison to ferrous slfate, has great efficacy for intestinal absorption and bio-utilization.

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Absorption and excretion of ¹⁴C-labeled midodrine were compared with those of ¹⁴C-DMAE, which is active metabolite of midodrine, after oral administration of each compound at equimolar dose (3.4 μmol/kg) in rats and dogs. Absorption of ¹⁴C-midodrine in rats has been shown to occur mainly from the intestine, and was faster than that of ¹⁴C-DMAE. During the process of absorption, DMAE was formed extensively by cleavage of the glycine molecule of midodrine. After oral administration of ¹⁴C-midodrine, the peak blood level of radioactivity was attained at 0.5 hr in rats and 1.25 hr in dogs, and was followed by a biexponential decline. In dogs given ¹⁴C-midodrine orally, the peak plasma level of unchanged midodrine, accounted for 14 % of total radioactivity, and was attained 0.75 hr after dosing, thereafter declined with a half-life of 4.71 hr. The active metabolite DMAE appeared in the plasma over the same period and the levels exceeded those of unchanged midodrine 0.75 hr after administration. The AUC value of DMAE (AUC_DMAE) after administration of ¹⁴C-midodrine was apparently higher than that after ¹⁴C-DMAE dosing in dogs. In both species, urinary excretion was the predominant elimination route accounting for 89.0 % of the dose in rats and 97.4 % in dogs during 5 days after dosing. Biliary excretion accounted for 28.7 % of the dose in rats within 30 hr after oral dosing. In addition, enterohepatic circulation was demonstrated. Similar excretion profiles were observed in the case of ¹⁴C-DMAE.

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Tissue distribution of ¹⁴C-midodrine and its active metabolite ¹⁴C-DMAE was investigated after oral and intravenous administration to rats using autoradiography and scintillation counting. Serum protein binding was also examined. After oral administration of ¹⁴C-midodrine at a dose of 3.4 μmol/kg, the radioactivity was distributed extensively throughout the body except for the central nervous system, testis and fat. High concentration of radioactivity was found in the gastrointestinal tract, liver and kidney followed by the lung, spleen, hypophysis and adrenal. The levels in these tissues were higher than that in the plasma. Elimination of radioactivity from tissues paralleled that of plasma, and no marked accumulation in any tissue was found. Although the tissue concentrations in early time after oral administration of ¹⁴C-midodrine were higher than that in the case of ¹⁴C-DMAE, the distribution profiles were essentially similar in each case. However, 5 min after intravenous administration of ¹⁴C-midodrine or ¹⁴C-DMAE, the distribution profiles were found to be different from each other. DMAE and other metabolites were found in the tissues after the administration of ¹⁴C-midodrine and only a small amount of unchanged drug was detected. Serum protein binding of ¹⁴C-midodrine or ¹⁴C-DMAE in vitro was 10 ?? 20 % in rats, rabbits and dogs, and 24 ?? 31 % in human. The extent of serum protein binding of radioactive substances was about 22 % at 0.5 hr after oral administration of ¹⁴C-midodrine to rats and was increased with time.

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Biotransformation of midodrine, 1-(2', 5'-dimethoxyphenyl)-2-glycinamidoethanol, developed as an α-adrenergic stimulant, was studied in rats. Eleven metabolites and only traces of the unchanged drug were detected in the 24 hr urine, in which 75.5 % of the dose was recovered after oral administration of ¹⁴C-midodrine (3.4 μmol/kg). The structures of the metabolites were elucidated by GC-MS analysis using an ion cluster technique and TLC in comparison with the corresponding authentic samples. The major metabolites were identified as 1-(2', 5'-dimethoxyphenyl)-2-aminoethanol (DMAE, M-1, 12.5 % of the dose), which is an active metabolite of midodrine, and 2'-methoxy-5'-hydroxyphenylglycol (M-4, 10.0 % of the dose). Other minor metabolites were also found as products of the oxidative deamination, O-demethylation and N-acetylation of DMAE. On the other hand, a fraction of midodrine administered was shown to be acetylated directly (M-7, 6.7 % of the dose) followed by O-demethylation (M-8, 9.5 % of the dose) without via an active metabolite DMAE. The phenolic metabolites, including M-2, M-4, M-8, M-10 were mainly presented in the urine and bile as sulfate conjugates. On the basis of these results, the metabolic pathways of midodrine in rats were discussed.

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Biotransformation of midodrine, 1-(2', 5'-dimthoxyphenyl)-2-glycinamidoethanol, was studied in dogs. After oral administration of ¹⁴C-midodrine (3.4 μmol/kg), urinary recovery was 81.0 % of the dose within 24 hr. The metabolites in the urine were analyzed by TLC and GC-MS in comparison with the corresponding authentic samples. Major metabolites were identified as 1-(2', 5'-dimethoxyphenyl)-2-aminoethanol (DMAE, M-1, 30.0 % of the dose) and 2', 5'-dimethoxymandelic acid (M-5, 20.8 % of the dose). Other minor metabolites included 2', 5'-dimethoxyphenylglycol (M-3) and 2'-methoxy-5'-hydroxyphenylglcol (M-4), mainly as their conjugates, and only the traces of the unchanged drug were detected. N-acetyl-midodrine and N-acetyl-demethyl-midodrine, found in the rat urine, have not been detected in dogs, suggesting that midodrine administered to dogs was completely converted into its active metabolite DMAE.

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The absorption, distribution and excretion of (−)-(2 S, 3 R)-2-amino-3-hydroxy-3-(3, 4-dihydroxyphenyl) propionic acid (L-DOPS), an unphysiological amino acid and the precursor of norepinephrine, were investigated in mice, rats, dogs and Rhesus monkeys after oral or intravenous administration of ¹⁴C-L-DOPS labelled at C-3 position.
1. When ¹⁴C-L-DOPS (10 mg/kg) was administered orally to male animals, the maximal concentration (C_max) in the serum was obtained within 1 hr after administration. C_max levels were 9.5, 4.4, 3.6 and 2.7 μg eq/ml in dogs, Rhesus monkeys, mice and rats, respectively. The serum levels decreased rapidly with halflives of 1.3 to 4.2 hr.
2. After single oral administration of 10, 100 or 1000 mg/kg of ¹⁴C-L-DOPS to male rats, the maximal serum concentration of radioactivity for all doses appeared within 1 hr and then decreased rapidly. The area under the serum concentration-time curve for ¹⁴C was closely correlated with the administered dose.
3. There was no difference in ¹⁴C serum levels between male and female rats.
4. The radioactivity was distributed throughout organs and tissues after single oral administration of ¹⁴C-L-DOPS (10 mg/kg) to animals. Then the ¹⁴C levels rapidly decreased and 24 hr after administration only tracer concentrations were observed in the tissues. No particular accumulation in specific tissues was found. Relatively high concentrations of ¹⁴C were found in the kidney and liver of every species, and in the pancreas of mice and rats.
5. When ¹⁴C-L-DOPS (10 mg/kg) was administered orally to male animals, the excretion of a radioactivity to urine and feces was 60 ?? 72 % and 9 ?? 20 % of administered dose, respectively. Male rats excreted 14 % of the administered dose with expired air. The male rats excreted with bile 2.8 % of the dose during 48 hr.

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Transdermal absorption of drugs, i.e. nitroglycerin and scoporamine, from marketed transdermal therapeutic systems (TTS) has been evaluated mainly according to T. Higuchi's theory. This theory, at first, was reviewed from the thermodynamic point of view. Much attention is paid to the enhanced transdermal absorption to expand the utility of TTS to many drugs and it becomes realistic by use of prodrugs as esters of viderabine, an antivirus drug, by the application of penetration-enhancers such as Azone, and/or by appearance of iontophoresis. Secondly, such enhancing systems were summarized theoretically and the differences between them and Higuchi's theory on the absorption rates were discussed. The route for transdermal absorption and its kinetic model might be modified in such enhancing systems, since the systems affect the skin barrier function. Reasonable absorption routes and skin model were discussed, thirdly. These three considerations could be useful for the development and evaluation of new TTS.

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The methods of sensitive drug detection by High Performance Liquid Chromatography (HPLC) are reviewed. The following conditions are advantageous for the sensitive detections: application of the columns with small theoretical plates, appropriate flow systems for surpression of peak broadening, and sensitive detection devices such as electrochemical, fluorometrical and luminometrical detection systems for HPLC. Finally, a different kinds of derivatization procedures for drugs for those systems are described.

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