The absorption, distribution, and excretion of radioactivity were studied in the male rat after a single dermal application of ¹⁴C-labeled FK506 ointment at an FK506 dose level of 1.6 mg/kg. The application period of the ointment was 24 hours.
1. Urinary and fecal excretion of radioactivity were 0.5 and 5.1% of the administered dose, respectively, over 168 hours after application to the intact skin under the non-occlusive dressing condition, 0.4 and 4.2% to the intact skin under the occlusive condition, and 2.4 and 53.8% to the damaged skin under the occlusive condition. Radioactivity remaining at the application site and in the animal body were respectively 14.6 and 0.3% at 168 hours after application to the intact skin under the non-occlusive condition, and were 4.7 and 0.4% after application to the damaged skin under the occlusive condition.
2. Radioactivity was not detected in the whole blood and plasma at any sampling points after ointment application to the intact dorsal skin under occlusive dressing condition. After application to the damaged dorsal skin under the occlusive condition, the pharmacokinetic parameters of radioactivity in the whole blood and plasma were respectively as follows: maximal concentration (C_max), 42.7 and 37.9 ng eq./mL; time to reach Cmax, both 2 hours; area under the concentration-time curve, 559 and 457 ng eq.·h/mL; and half life, 9.0 and 9.3 hours.
3. After ointment application to the damaged dorsal skin under the occlusive dressing condition, rank order of radioactivity detected at 30 minutes after application was as follows: lung and adrenal gland>brown fat, heart, thyroid gland, kidney, liver and spleen>plasma, urinary bladder and eyeball>cerebrum and testis. The maximal level of radioactivity was observed between 1/2 and 2 hours after application in most tissues. The proportion of radioactivity at 72 hours after application of the maximal level was less than 0.1 in all tissues except the urinary bladder where the proportion was 0.94.

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The pharmacokinetics of tacrolimus (FK506) were studied in the male rat after a single dermal application of FK506 ointment over an application period of 24 hours. In the typical experiment, the amount of ointment applied was 100 mg per each rat, and application area was 10 cm². The pharmacokinetic parameters estimated were maximal blood concentration (C_max), time to reach C_max (T_max), and area under the blood concentration-time curve (AUC).
1. Blood concentrations of FK506 were determined after a single dermal application of FK506 ointment under the occlusive or non-occlusive dressing condition. After respective application of 0.5 and 0.1% FK506 ointment to the intact and damaged skin, C_max and AUC values did not differ significantly between either dressing conditions. Blood concentrations of FK506 after a single dermal application of FK506 ointment to the damaged skin were much higher than those applied to the intact skin. The bioavailability of FK506 after application of 0.5% FK506 ointment to the intact skin was 5% and that to the damaged skin was 62%.
2. After a single dermal application of 0.03, 0.1 and 0.5% FK506 ointment to the intact skin, the C_max and AUC values increased in proportion to the strength of the ointment. After a single dermal application of 0.3% FK506 ointment to 2.5, 5 and 10 cm₂ of the intact skin, the C_max and AUC values increased proportionally to the area of the skin. The C_max and AUC values did not the differ significantly after single dermal application of 10, 30, 100 and 300 mg of 0.3% FK506 ointment to the intact skin.

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To examine whether the retention of imidazole analogues in the organ rich with elastic connective tissue can be of toxicological significance, the effect of ¹⁴C labeled 2-methylimidazole (2MI) as a model compound on the mechanical, biochemical, and morphological properties of the rat aorta, together with its irreversible interaction with the tissue macromolecules, was investigated after chronic treatment during maturation (10 and 100 μmol/kg/day for 28 days, from 4 to 8 weeks of age, subcutaneous injection).
1. Aortic extensibility was significantly decreased in 2MI-dose-dependent manner, whereas tensile strength showed an increasing trend.
2. Aortic elastin content was decreased dose-dependently, while collagen content was increased.
3. The low dose of 2MI scarcely altered histological picture of the aortic wall compared to the control group (isotonic saline dosing), but the high dose caused focal disorganization and fragmentation of the medial elastic laminae. Thickness of the aortic media showed a dose-dependent increasing trend.
4. The level of irreversibly bound 2MI-equivalent in elastin fraction was considerably high as compared with that in non-elastin fraction, and was increased dose-dependently. The aortic microautoradiograph showed that [¹⁴C]2MI-derived radioactivity occurred in the media, the region rich with elastic fiber.
These findings indicate that 2MI affects maturation of the elastic organ materially, and that the effect can be closely linked with the binding of 2MI to elastin. It is possible that the same holds true for some other imidazole-based compounds that are retained in large quantities in the elastic connective tissue.

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WinPBPK is a computer program for the analysis of drug distribution in the body which utilizes a physiologically-based pharmacokinetic model, where linear ordinary differential equations are numerically solved by the Runge-Kutta-Gill method. This program is written in Visual BASIC (VB) language. Since VB runs under Windows and has a high level user interface, WinPBPK is available to all DOS/V IBM compatible computers. Numerically solved tissue or organ drug concentrations vs. time data are shown on the CRT display as concentrations vs. time curves and thereafter are saved on hard disk. These numerical data can also be shown as simulated image whole body autoradiograms where drug concentrations in all the tissues or organs are converted to monochrome or full color image data. These image data can be visually compared to that obtained by real autoradiography using ¹⁴C-labelled drug. The system was applied to the pharmacokinetic analysis of tacrolimus, an immunosuppressant, in rats. The PBPK model for tacrolimus was developed with 17 tissues and organs including lung, blood, brain, heart, liver, pancreas, spleen, intestine, kidneys, gall bladder, thyroid, fat tissue, muscle, testes, bone and skin. The exchange rate of the amount of drug in each tissue or organ was described with differential equations using physiological parameters, biochemical parameters and pharmacokinetic parameters. The simulated image autoradiograms of tacrolimus at 15 min, 1 hr, 3 hr, and 8 hr after iv bolus injection to rats, 1 mg/kg, were compared with the autoradiograms of ¹⁴C tacrolimus being injected to rats, 1 mg/kg. There was good correlation between the simulated image autoradiograms and the real ones. By means of this software, the predicted pattern of drug distribution to the tissues and organs based on the PBPK model analysis can be compared visually to the real autoradiogram.

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¹⁴C-プロムフェナクナトリウム点眼液を雄性白色ウサギの両眼に0.1mg/animal(0,05mg/50μl/eye)の割合で単回あるいは反復点眼投与し，吸収，分布および代謝について検討した．
1．単回点眼後における血漿中放射能濃度は投与後30分に最高濃度113.2ng eq./mlを示したのち，1時間から12時間まで半減期2.2hrで消失した．眼組織内放射能濃度は約半数の組織が投与後30分に最高濃度を示した．組織への分布は角膜に最も高い濃度が認められ，ついで前部強膜および結膜に高かった．水晶体および硝子体の濃度は最も低かった．投与後72時間では水晶体で最高濃度の7%を示したものの，他の組織ではすべて検出限界以下であった．
2．反復点眼期間中における血漿中放射能濃度は1回投与後24時間では検出限界以下であったが，7回投与以降，投与回数に伴って緩慢に上昇し，21回投与までにほぼ定常状態に達した．また1，7，14および21回投与後24時間の眼組―織内放射能濃度は一部の組織を除いて投与回数に伴って上昇したが，21回投与までにほぼ定常状態に達した．水晶体および後部強膜では21回投与後には1回投与後の4.0および1.6倍の濃度を示した．21回投与後の血漿および眼組織からの放射能の消失は単回投与群と比較してやや緩慢であった．
3．単回点眼後1，2および4時間に得られた前房水中には未変化体が前房水中放射能の73.0～79.5%が認められた．代謝物としてプロムフェナクのcarboxymethyl基が酸化されてbenzoic　acid誘導体に変換されたAHR-11665およびその前駆体であるWAY-127039-A-1，また分子内環化して2-oxyindole誘導体に変換されたAHR-10240およびisatine誘導体のAHR-11652が検出された．血漿中には単回点眼後1，2および4時間に未変化体が血漿中放射能の76.7～80.5%が認められた．代謝物として前房水中に認められた代謝物のほか，未知代謝物1RaP1，1RaP2および1RaP3が検出された．

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Radioluminography (RLG) has been developed as one of the two-dimensional radiodetection techniques and widely applied to the drug evaluation studies. As the validation items of RLG, 1) the uniformity examination in fl-ray sensitivity, 2) the evaluation of background PSL value (PSL_BG) and monitoring radioactive contamimination of IP, and 3) the accurate expression of radioactivity in Bq instead of PSL were pointed out. The uniformity in β-ray sensitivity was examined by analyzing the IPs exposed to a planar ¹⁴⁷Pm radiation source. A small but definite non-unifomiry in sensitivity was observed, which could be attributed to the mechanics of BAS. New methods for accurately evaluating PSL_BG and monitoring radioactive contamination of IP were proposed. The usefulness of microplate-RLG as off-line counting of HPLC was emphasized. A new radiographic method that images the density distribution of lyophilized animal sections of WBA was described. This technique made it possible to measure the thickness (mg/cm²) of each tissue and correct the self absorption of β-ray, and thereby opened a road to a genuine quantitative WBA.

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