Trimoprostil [11 R, 16, 16-trimethyl-15 R-hydroxy-9-oxoprosta-cis-5-trans-13-dienoic acid] labeled with either ³H or ¹⁴C was orally administered to rats (100 μg/kg) to examine blood level profile, tissue distribution, excretion and reabsorption.
The blood peak level occurred within 45 min then the concentration followed a biphasic decline; t_1/2 from the peak time to 3 hr was 1.1-1.6 hr and t_1/2 from 3 to 24 hr was 5.2-5.9 hr. The intact drug comprised 30-40 % of total radioactivity during the first 4 hr. The liver, kidney and GIT wall were the organs containing a high radioactivity.
Approximately 90 % of the administered radioactivity was recovered from the urine and feces during 24 hr postdosing period. Biliary excretion was as high as 80-90 %.

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³H-trimoprostil labeled at a C-11 methyl position was repeatedly given to rats of two sexes at a daily oral dose of 100 μg/kg for 14 days. The blood level profile and tissue accumulation of radioactivity were examined during and after the multiple administration.
1. Blood level profile
The time course of ³H in the blood showed two peaks, one approximately 30 ?? 45 min and another 4 hr after respective dosing, then the blood concentration gradually decreased.
The peak and minimum concentrations (24 hr level after each dosing) during the multiple administration were in the range of 1 ?? 2.1 times and 2.4 ?? 3.6 times higher than those observed after a single administration respectively.
2. Tissue accumulation
The accumulation ratio (a ratio of concentration of ³H at 24 hr after the last dose of multiple administration, over 24 hr concentration after a single dosing) in each tissue was the same or lower in comparison to that (3.6 ?? 10) of the blood.
Within 21 days after the cessation of multiple administration, ³H concentration in almost all the tissues other than the white fat pad decreased below the respective detection limits or 24 hr-levels after a single administration (100 μg/kg). The concentration of ³H in the fat pad on Day 21 after the last dose was as low as 20 ?? 24%of the level on day 1.

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1. Excretion into the milk
³H-Trimoprostil labeled at a C-11 methyl position was given to lactating rats at a single oral dose of 100 μg/kg to examine excretion of total radioactivity into the milk.
Not only total radioactivity but also intact trimoprostil are unlikely to be subjected to an active transfer from the blood to the milk.
2. Foeto-placental transfer
On the 14 th and 19 th gestation day ³H-trimoprostil was orally given to pregnant rats (100 μg/kg) to examine foeto-placental transfer.
Both the total radioactivity and the intact drug were effectively blocked by foetoplacental barrier on Day 14 and 19 of gestation.

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A tape formulation (NT-1) containing glyceryl trinitrate (GTN) to increase its bioavailability and to avoid the first-pass effect in a liver was applied to the dog and the human, and then GTN, 1, 2-glyceryl dinitrate (GDN) and 1, 3-GDN in the blood was determined simultaneously by gas chromatography/negative ion chemical ionization-mass spectrometry (GC/NICI-MS). The blood concentration in dogs and human beings was as follows 1, 2-GDN>1, 3-GDN> GTN, and the absorption rate from the skin in the human beings was 10.8-12.2 times higher than that of the dog. The concentration of GTN in the dog reached a steady-state at 2 hours after the application of NT-1, and it was kept the level of 1 ng/ml of plasma until the final time of administration. After the exfoliation the blood concentration of GTN diminished rapidly. The concentration of GTN in human blood reached to a maximum level at 2 hrs after application of NT-1, and then it decreased slowly to 30-80 % of the maximum concentration following the exfoliation of the tape. After the exfoliation the blood level of GTN in human diminished rapidly to 1/2-1/5 of the concentration at the final time of administration. The blood pressure was related to the blood concentration of GTN, both in dogs and humans. This tape is highly safe and useful for the sustained release for a long time, and it is predicted to be effective to prevent an angina pectoris and to cure an acute cardiac failure.

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The metabolism of flutoprazepam (FP) and fludiazepam (FD) in mice, in vitro and in vivo, was investigated. In vitro experiments with mouse liver 9, 000 × g supernatant have shown that FP was mainly metabolized to N-desalkylflutoprazepam (DFP) and 3-hydroxyflutoprazepam (HFP), wheares 3-hydroxyfludiazepam (HFD) was the major metabolite in the case of FD when used substrate concentrations were high (more than 100 μM). The N₁-dealkylation activity of the liver 9, 000 × g supernatant for FP was approximately four times higher than that for FD, but the C₃-hydroxylation activity for FP was one-half of that of FD at 100 μM of substrate concentration. When substrate concentrations were low (2.5 ?? 10 μM), FP was mainly metabolized to DFP, and HFP was not detected. In the case of FD, approximately equal amounts of DFP and HFD were generated. In both substrates, N-desalkyl-3-hydroxyflutoprazepam (DHF) was the minor metabolite.
FP and FD were also administered orally (0.64 mg/kg) to mice and plasma concentrations of metabolites were determined. When FP was administered, DFP and DHF were the major metabolites, and FP and HFP were below the detection limit. The similarity of the metabolites detected in plasma during in vivo experiments to those formed in vitro, at low substrate concentrations, was observed in FP. In the case of FD, the major metabolites in plasma were also DFP and DHF, but a small amount of FD and HFD were detected at the early period of time after administration. These results were also explained by observations that the in vitro metabolic rate of FD was slower than that of FP, that C₃-hydroxylation activity for FD was higher than that for FP, and that the fraction of DFP to total metabolites at low substrate concentrations was increased more than that at high concentrations.

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In order to understand dynamically the drug transport and disposition in the brain, it is important to obtain the kinetic parameters representing the individual rate process. The rate processes which should be considered are influx from blood to brain, efflux from CSF (or brain) to blood, diffusion in extracellular space, exchange between intracellular space and extracellular space, and intracellular binding and metabolism. In this minireview, several methods to obtain the influx and efflux rate constants were summarized and the advantages and limitations of each method were discussed. The methods include not only in vivo and in situ methods but also in vitro experimental system using isolated microvessel (brain capillary) and choroid plexus which might possibly be suitable for screening the influx and efflux permeability of drugs, respectively. Of most importance finally is to construct a kinetic model to predict the time course of drug concentrations in various regions of brain by incorporating thus obtained kinetic parameters. The concepts developed in the field of physiological pharmacokinetic modeling might be helpful to fulfill this purpose.

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