Pharmacokinetics of famciclovir, a prodrug of an antiherpes compound BRL39123, was studied following a single and repeat oral administration of famciclovir to healthy Japanese volunteers.
The active metabolite BRL39123 appeared in plasma at 0.5 hours after single ad ministration of famciclovir at 250, 500 and 1000 mg, reached C_max in 2 hours and decreased with T_1/2 of 1.84-2.03 hours. The C_max and AUC_0-∞ values of BRL39123 increased in proportion to the dose levels studied. The urinary excretions (% of dose) of BRL39123 and BRL42359 over 24 hours after administration were 53.35-60.92% and 5.06-6.40%, respectively, with no significant difference among the doses. Thus the pharmacokinetics of famciclovir after a single oral administration was linear in the dose range from 250 to 1000 mg.
When famciclovir 750 mg was administered once a day on Days 1 and 7, and three times a day at 5-hour intervals on Days 2 to 6, no significant difference was detected in either AUC_0-∞ or C_max between Days 1 and 7. During the repeated administration, the plasma concentration of BRL39123 immediately before the first administration of the next dosing day was near or below the limit of reliable determination, indicating no accumulation by the repeat administration. There was no significant difference in T_max or T_1/2 between Days 1 and 7. The urinary excretions of BRL39123 and total metabolites determined were statistically not different between Days 1 and 7, and also between Day 1 and through the administration period. Hence, there was no evidence for drug accumulation and for alternation of the pharmacokinetics of famciclovir by the repeat dose regimen studied.

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Blood or plasma concentration, distribution, metabolism and excretion of E6010 were studied in male rats after a single intravenous administration of ¹²⁵I-E6010 in comparison with ¹²⁵I-rt-PA.
1. After a single intravenous administration of ¹²⁵I-E6010, plasma clearances of TCA-precipitable radioactivity, immunoreactivity, fibrinolytic activity and the unchanged E6010 were 10.3, 11.2, 3.1 and 5.5 times lower than those after dosing of ¹²⁵I-rt-PA, respectively.
In the plasma, the complexes of ¹²⁵I-E6010 with α₂-macroglobulin and with α₂-plasmin inhibitor were observed after dosing of ¹²⁵I-E6010, as well as after dosing of ¹²⁵I-rt-PA.
2. After a single intravenous administration of ¹²⁵I-E6010, liver levels of TCA-precipitable radioactivity reached maximum level at 15 min after administration accounting for about 19% of administered radioactivity. In the case of ¹²⁵I-rt-PA, it reached maximum level at 5 min accounting for about 54% of administered dose. These results suggest that the differences in the distribution to the liver between E6010 and rt-PA resulted in the difference of plasma clearances.
3. Within 7days after a single int ravenous administration of ¹²⁵I-E6010, 96.05% and 5.32% of the administered radioactivity were excreted into urine and feces, respectively. Biliary excretion of radioactivity was 17.01% of the dose within 48hr after a single intravenous administration of ¹²⁵I-E6010. Both radioactivity excreted in urine and in bile consisted almost of small molecular weight metabolites or free ¹²⁵I.

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Blood or plasma concentration, distribution, metabolism and excretion of E6010 were studied in male rats during and after repeated daily intravenous administration of 0.4 mg/kg of ¹²⁵I-E6010 for 10 days.
1. At 5 min after the repeated intravenous administration of ¹²⁵I-E6010 for 10 days, blood or plasma levels of total and TCA-precipitable radioactivity, immunoreactive E6010 and the unchanged E6010 and its metabolites were the same as those at 5 min after a single dosing. After the repeated intravenous administration of ¹²⁵I-E6010 for 10 days, the levels of total and TCA-precipitable radioactivity in the blood or plasma decreased slower than those after a single administration, but the levels of immunoreactive E6010 and unchanged E6010 were the same as those after a single administration.
2. TCA-precipitable radioactivity level at 24 hr afte r the last dosing in most tissues did not exceed the levels after a single dose by 3 times, except in spleen (3.7 times), bone marrow (3.7 times) and thyroid (3.2 times). After repeated intravenous administration of ¹²⁵I-E6010, the levels of total and TCA-precipitable radioactivity in each tissue decreased slower than those after a single dosing, but the levels of the immunoreactive E6010 in the liver and kidney were the same as those after a single dosing.
3. The excretion of radioactivity in the urine and feces was nearly the same th roughout the period of repeated intravenous administration of ¹²⁵I-E6010. Within 7 days after the last dosing, 92.42% and 7.74% of the administered radioactivity was excreted into the urine and feces, respectively. Radioactivity excreted in the urine after the last dosing consisted almost of small molecular weight metabolites or free ¹²⁵I, similar to that after a single administration.

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The feto-placental transfer of ¹²⁵I-E6010 and the excretion into milk were studied in pregnant and lactating rats after a single intravenous administration of 0.4 mg/kg of ¹²⁵I-E6010.
1. At 15 min after a single intravenous administration of ¹²⁵I-E6010 to rats on day 13 and 19 of gestation, the radioactivity level in the fetus was 245 ?? 348 times lower than that present in maternal plasma, but most of that was not TCA-precipitable. At later time on day 19 of gestation, the level of radioactivity in the fetal thyroid tissue was higher than that in the other fetal and maternal tissues, however, it was suggested that radioactivity in the thyroid results from the accumulation of free ¹²⁵I. These results suggested that ¹²⁵I-E6010 administered to pregnant rats was not transfered into the fetus as an intact E6010.
2. After a single intravenous administration of ¹²⁵I-E6010 to lactating rats, the TCA-precipitable radioactivity was found in the milk, and its level increased and reached maximum at 24 hr, but the immunoreactive E6010 was not detected at any time. Then, most of the radioactivity in the milk was considered to be an endogeneous high molecular weight compounds into which a free iodine, produced by degradation of ¹²⁵I-E6010, was incorporated.

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The absorption, distribution and excretion of [¹²⁵I]lecithin bound iodine (LBI) were investigated in male rats after daily oral administration of 10 mg as iodine/kg for 7 days.
1. Concentration of iodine in the blood at 3 hr after daily dosing reached a steady state by the second dosing. At 24 hr after daily dosing, concentration of iodine was low and did not change with the number of doses. Concentration of iodine after the 7th dosing reached a maximum of 11.16 μg eq./ml at 1 hr and then declined with half lives of 6.7 and 23 hr at the observation periods of 3-12 hr and 24-72 hr, respectively.
2. At 24 hr after the 7th dosing, concentration of iodine in the thyroid gland was 415 times higher and those in the stomach, skin, fat, brown fat and bone marrow were 2-9 times higher, and those in the other tissues were similar to or lower than the concentration in the plasma. Elimination of iodine from tissues was comparably rapid. At 336 hr after the 7th dosing, concentration of iodine in the thyroid gland decreased to 66% of that found at 24 hr and those in the fat and epididymis were 37 and 33%, respectively, of those found at 24 hr. Concentrations in the other tissues were less than 22% of those found at 24 hr or below the detection limit. Whole body autoradiograms showed the similar distribution to the above findings. Distribution of iodine in blood cells was low, being about 33% and did not change with time.
3. Excretion ratios of iodine up to 24 hr after daily dosing in urine and feces were about 90 and 10% of the cumulative dose, respectively, and did not change with the increase in the number of doses.
From the above findings, iodine in blood was specifically distributed to the thyroid gland al ready at 4 hr after dosing, and still remained markedly at 336 hr after dosing. The time course of iodine in the other tissues was parallel to that in the plasma, indicating no tendency to accumulate or remain.

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The absorption, distribution, metabolism and excretion of ¹⁴C-tulobuterol or unlabeled tulobuterol following a single dermal application was examined in rats.
1. After a single dermal application of a tape containing ¹⁴C-tulobuter ol at 10 mg/kg, blood radioactivity reached maximum at 2 and 4 hr in male and female rats, respectively. Radioactivity decreased with T₂ of 15.9 and 15.7 hr in male and female rats, respectively.
2. After a single dermal application of unlabeled tulobuterol at 5, 10 and 20 mg/kg to male rats, blood levels of unchanged tulobuterol reached maximum at 4.0-5.5 hr and then disappeared with T₂ of 2.6-2.9 hr.The bioavailability of tulobuterol was about ten times that after an oral administration. C_max and AUC increased in dose-dependent manner within a dose range of 5-20 mg/kg.
3. After a single dermal application of ¹⁴C-tulobuterol to male rats, radioactivity in nearly all tissues reached maximum at 4 hr. The radioactivity was distributed well in target organs such as lung and trachea, and was particularly high in the skin at the site of application followed by liver and kidney.
4. Metabolites in urine after a subcutaneous dose of tulobuterol were essentially the same as after an oral administration. The unchanged tulobuterol increased from 0.1 to 3.1% of the dose when the route of administration was changed from oral to subcutaneous.
5. After a single dermal applic ation of ¹⁴C-tulobuterol at 10 mg/kg, urinary and fecal excretions of radioactivity within 168 hr were 50.8 and 35.4% in male rats and, 52.8 and 34.7% in female rats, respectively. Recovery in urine and feces and from residue in the tape was almost complete in the male (99.5%) and female (100.3%) rats.

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The absorption, distribution and excretion of ¹⁴C-tulobuterol following daily dermal application at 10 mg/kg for 7 days was examined in rats.
1. Blood radioactivity reached a steady state after the 4th dose. After the final dose, blood radioactivity showed maximum values of 506.1 ng eq./ml at 5 hr and disappeared with T_1/2 of 19.4 hr as also noted for T_1/2 after a single application (15.7 hr).
2. After the final application, the radioactivity in most tissues was higher than after a single application. Elimination of radioactivity in tissue was basically the same as after a single application.
3. Within 168 hr after the 7th application, urinary and fecal excretion was 53.8 and 36.3% of the dose, respectively. Recovery in urine and feces and from residue in the removed tape was 98.6% of the dose.

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The absorption, distribution and excretion of ¹⁴C-tulobuterol or unlabeled tulobuterol following a single application was examined in infant rats.
1. After a single dermal application of a tape containing ¹⁴C-tulobuterol at 10 mg/kg, blood radioactivity reached maximum at 4 hr in male and female infant rats, respectively. Radioactivity disappeared with T_1/2 of 17.0 and 17.3 hr in male and female infant rats, respectively.
2. After a single dermal application of unlabeled tulobuter ol at 5, 10 and 20 mg/kg to male infant rats, blood levels of unchanged tulobuterol reached maximum at 4.0 hr and then disappeared with T_1/2 of 2.8-2.9 hr. C_max and AUC increased dose-dependently within a dose range of 5-20 mg/kg.
3. After a single dermal application of ¹⁴C-tulobuterol to male infant rats, the radioactivity in nearly all tissues reached maximum at 4 hr. Radioactivity was distributed well in target organs such as the lung and trachea, and was particularly high in the skin at the site of application followed by the liver and kidney.
4. After a single dermal application of ¹⁴C-tulobuterol at 10 mg/kg, the urinary and fecal excretion of radioactivity within 168 hr was 50.1 and 30.5% in male infant rats and, 52.5 and 32.2% in female infant rats, respectively. Recoveries in urine and feces and from residue in the removed tape was almost complete in male (99.4%) and female (98.5%) rats.

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Although passive diffusion, which depends on the lipid solubility, is a fundamental mechanism for the membrane transport of many of compounds, water-soluble compounds also cross cell membranes by the specialized carrier-mediated transport mechanisms. We have demonstrated that several drugs are transported by the tissue-specific transporters in intestinal and renal epithelial cells, hepatocytes and brain capillary endothelial cells which form the blood-brain barrier. They include oligopeptide transporter, monocarboxylic acid transporter, anion antiporter, organic anion transporter, and P-glycoprotein. Most of them functions for the uptakes of drugs into the cells leading to the increased permeability, others exclude drugs out of cells, thereby decreasing apparent permeability into cells. It was also found that a certain drug which crosses by the certain transporter in the intestinal membranes is sometimes recognized by the other transporter, or not recognized by transporters in other tissues. This finding demonstrates that it would be possible to expect tissue specific delivery of drugs by utilizing transporters which have different characteristics among tissues. Such a difference in permeability among tissues would be difficult to expect when the membrane transport is carried out by passive diffusion. There are more evidences for carrier-mediated transport of many drugs in various tissues other than mentioned in the present study. Further mechanistic clarification and quantitative analysis of pharmacokinetic importance of such transporters will help the development of effective strategies for the site specific drug delivery.

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